Vacuolar processing enzyme translocates to the vacuole through the autophagy pathway to induce programmed cell death.
Abstract The caspase-like vacuolar processing enzyme (VPE) is a key factor in programmed cell death (PCD) associated with plant stress responses. Growth medium lacking a carbon source and dark conditions caused punctate labeling of 35S::VPE1-GFP (StVPE1-GFP) in potato leaves. Under conditions of carbon starvation, VPE activity and PCD symptoms strongly increased in BY-2 cells, but to a much lesser extent in VPE-RNAi BY-2 cells. During extended exposure to carbon starvation, VPE expression and activity levels peaked, with a gradual increase in BY-2 cell death. Histological analysis of StVPE1-GFP in BY-2 cells showe...
Source: Autophagy - November 29, 2020 Category: Cytology Authors: Teper-Bamnolker P, Danieli R, Peled-Zehavi H, Belausov E, Abu-Abied M, Avin-Wittenberg T, Sadot E, Eshel D Tags: Autophagy Source Type: research

A high-throughput screening identifies ZNF418 as a novel regulator of the ubiquitin-proteasome system and autophagy-lysosomal pathway.
In conclusion, our study provides evidence that ZNF418 activates the ALP, inhibits the UPS and regulates genes associated with cardiomyocyte structure/function. PMID: 33249983 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - November 29, 2020 Category: Cytology Authors: Singh SR, Meyer-Jens M, Alizoti E, Bacon WC, Davis G, Osinska H, Gulick J, Reischmann-Düsener S, Orthey E, McLendon PM, Molkentin JD, Schlossarek S, Robbins J, Carrier L Tags: Autophagy Source Type: research

Analysis of Drosophila Atg8 proteins reveals multiple lipidation-independent roles.
acute;th GV, Sinka R, Juhász G Abstract Yeast Atg8 and its homologs are involved in autophagosome biogenesis in all eukaryotes. These are the most widely used markers for autophagy thanks to the association of their lipidated forms with autophagic membranes. The Atg8 protein family expanded in animals and plants, with most Drosophila species having two Atg8 homologs. In this Brief Report, we use clear-cut genetic analysis in Drosophila melanogaster to show that lipidated Atg8a is required for autophagy, while its non-lipidated form is essential for developmentally programmed larval midgut elimination and vi...
Source: Autophagy - November 29, 2020 Category: Cytology Authors: Jipa A, Vedelek V, Merényi Z, Ürmösi A, Takáts S, Kovács AL, Horváth GV, Sinka R, Juhász G Tags: Autophagy Source Type: research

A multifactorial score including autophagy for prognosis and care of COVID-19 patients.
abi B Abstract In less than eleven months, the world was brought to a halt by the COVID-19 outbreak. With hospitals becoming overwhelmed, one of the highest priorities concerned critical care triage to ration the scarce resources of intensive care units. Which patient should be treated first? Based on what clinical and biological criteria? A global joint effort rapidly led to sequencing the genomes of tens of thousands of COVID-19 patients to determine the patients' genetic signature that causes them to be at risk of suddenly developing severe disease. In this commentary, we would like to consider some points conc...
Source: Autophagy - November 29, 2020 Category: Cytology Authors: Domdom MA, Brest P, Grosjean I, Roméo B, Landi MT, Gal J, Klionsky DJ, Hofman P, Mograbi B Tags: Autophagy Source Type: research

Selective Autophagy: the Rise of the Zebrafish Model.
Abstract Selective autophagy is a specific elimination of certain intracellular substrates by autophagic pathways. The most studied macroautophagy pathway involves tagging and recognition of a specific cargo by the autophagic membrane (phagophore) followed by the complete sequestration of targeted cargo from the cytosol by the double-membrane vesicle, autophagosome. Until recently, the knowledge about selective macroautophagy was minimal, but now there is a panoply of links elucidating how phagophores engulf their substrates selectively. The studies of selective autophagy processes have further stressed the import...
Source: Autophagy - November 24, 2020 Category: Cytology Authors: Pant DC, Nazarko TY Tags: Autophagy Source Type: research

GLIPR2 is a negative regulator of autophagy and the BECN1-ATG14-containing phosphatidylinositol 3-kinase complex.
In this study, we used CRISPR-Cas9-mediated depletion of GLIPR2 in cells and mice to investigate the role of GLIPR2 in the regulation of autophagy and PtdIns3K-C1 activity. Depletion of GLIPR2 in HeLa cells increased autophagic flux and generation of phosphatidylinositol 3-phosphate (PtdIns3P). GLIPR2 knockout resulted in less compact Golgi structures, which was also observed in autophagy-inducing conditions such as amino acid starvation or Tat-BECN1 peptide treatment. Importantly, the binding of GLIPR2 to purified PtdIns3K-C1 inhibited the in vitro lipid kinase activity of PtdIns3K-C1. Moreover, the tissues of glipr2 knoc...
Source: Autophagy - November 23, 2020 Category: Cytology Authors: Zhao Y, Zou Z, Sun D, Li Y, Sinha SC, Yu L, Bennett L, Levine B Tags: Autophagy Source Type: research

A tecpr2 knockout mouse exhibits age-dependent neuroaxonal dystrophyassociated with autophagosome accumulation.
Abstract Mutations in the coding sequence of human TECPR2 were recently linked to spastic paraplegia type 49 (SPG49), a hereditary neurodegenerative disorder involving intellectual disability, autonomic-sensory neuropathy, chronic respiratory disease and decreased pain sensitivity. Here, we report the generation of a novel CRISPR-Cas9 tecpr2 knockout (tecpr2 -/-) mouse that exhibits behavioral pathologies observed in SPG49 patients. tecpr2 -/- mice develop neurodegenerative patterns in an age-dependent manner, manifested predominantly as neuroaxonal dystrophy in the gracile (GrN) and cuneate nuclei (CuN) of the me...
Source: Autophagy - November 20, 2020 Category: Cytology Authors: Tamim-Yecheskel BC, Fraiberg M, Kokabi K, Freud S, Shatz O, Marvaldi L, Subic N, Brenner O, Tsoory M, Eilam-Altstadter R, Biton I, Savidor A, Dezorella N, Heimer G, Behrends C, Ben-Zeev B, Elazar Z Tags: Autophagy Source Type: research

Alternative mitochondrial quality control mediated by extracellular release.
Abstract Mitochondrial quality control, which is crucial for maintaining cellular homeostasis, has been considered to be achieved exclusively through mitophagy. Here we report an alternative mitochondrial quality control pathway mediated by extracellular mitochondria release. By performing time-lapse confocal imaging on a stable cell line with fluorescent-labeled mitochondria, we observed release of mitochondria from cells into the extracellular space. Correlative light-electron microscopy revealed that majority of the extracellular mitochondria are in free form and, on rare occasions, some are enclosed in membran...
Source: Autophagy - November 20, 2020 Category: Cytology Authors: Choong CJ, Okuno T, Ikenaka K, Baba K, Hayakawa H, Koike M, Yokota M, Doi J, Kakuda K, Takeuchi T, Kuma A, Nakamura S, Nagai Y, Nagano S, Yoshimori T, Mochizuki H Tags: Autophagy Source Type: research

MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis.
Abstract The function of mitophagy in cancer is controversial. ULK1 is critical for induction of macroautophagy/autophagy and has a more specific role in mitophagy in response to hypoxia. Here, we show that ULK1 deficiency induces an invasive phenotype of breast cancer cells under hypoxia and increases osteolytic bone metastasis. Mechanistically, ULK1 depletion attenuates mitophagy ability during hypoxia. As a result, the accumulation of damaged, ROS-generating mitochondria leads to activation of the NLRP3 inflammasome, which induces abnormal soluble cytokines secretion, then promotes the differentiation and matur...
Source: Autophagy - November 19, 2020 Category: Cytology Authors: Deng R, Zhang HL, Huang JH, Cai RZ, Wang Y, Chen YH, Hu BX, Ye ZP, Li ZL, Mai J, Huang Y, Li X, Peng XD, Feng GK, Li JD, Tang J, Zhu XF Tags: Autophagy Source Type: research

Lysosomal targeting of autophagosomes by the TECPR domain of TECPR2.
Abstract TECPR2 (tectonin beta-propeller repeat containing 2) is a large, multi-domain protein comprised of an amino-terminal WD domain, a middle unstructured region and a carboxy-terminal TEPCR domain comprises of six TECPR repeats followed by a functional LIR motif. Human TECPR2 mutations are linked to spastic paraplegia type 49 (SPG49), a hereditary neurodegenerative disorder. Here we show that basal macroautophagic/autophagic flux is impaired in SPG49 patient fibroblasts in the form of accumulated autophagosomes. Ectopic expression of either full length TECPR2 or the TECPR domain rescued autophagy in patient f...
Source: Autophagy - November 19, 2020 Category: Cytology Authors: Fraiberg M, Tamim-Yecheskel BC, Kokabi K, Subic N, Heimer G, Eck F, Nalbach K, Behrends C, Ben-Zeev B, Shatz O, Elazar Z Tags: Autophagy Source Type: research

Pancreas-specific SNAP23 Depletion Prevents Pancreatitis by Attenuating Pathological Basolateral Exocytosis and Formation of Trypsin-activating Autolysosomes.
This study revealed the roles of SNAP23 in mediating pathological basolateral exocytosis and IKBKB/IKKβ's involvement in autolysosome formation, both where trypsinogen activation would occur to cause pancreatitis. SNAP23 is a strong candidate to target for pancreatitis therapy. PMID: 33213278 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - November 19, 2020 Category: Cytology Authors: Dolai S, Takahashi T, Qin T, Liang T, Xie L, Kang F, Miao YF, Xie H, Kang Y, Manuel J, Winter E, Roche PA, Cattral MS, Gaisano HY Tags: Autophagy Source Type: research

Enhanced viability and function of mesenchymal stromal cell spheroids is mediated via autophagy induction.
In this study, we investigated the molecular mechanisms by which MSC3D gain the potential for enhanced cell viability. Herein, we found that macroautophagy/autophagy was highly induced and ROS production was suppressed in MSC3D as compared to 2D-cultured MSCs (MSC2D). Interestingly, inhibition of autophagy induction caused decreased cell viability and increased apoptotic activity in MSC3D. Furthermore, modulation of ROS production was closely related to the survival and apoptosis of MSC3D. We also observed that HMOX1 (heme oxygenase 1) was significantly up-regulated in MSC3D. In addition, gene silencing of HMOX1 caused upr...
Source: Autophagy - November 18, 2020 Category: Cytology Authors: Regmi S, Raut PK, Pathak S, Shrestha P, Park PH, Jeong JH Tags: Autophagy Source Type: research

TXNIP/VDUP1 attenuates steatohepatitis via autophagy and fatty acid oxidation.
Abstract Impaired macroautophagy/autophagy has been implicated in experimental and human nonalcoholic steatohepatitis (NASH). However, the mechanism underlying autophagy dysregulation in NASH is largely unknown. Here, we investigated the role and mechanism of TXNIP/VDUP1 (thioredoxin interacting protein), a key mediator of cellular stress responses, in the pathogenesis of NASH. Hepatic TXNIP expression was upregulated in nonalcoholic fatty liver disease (NAFLD) patients and in methionine choline-deficient (MCD) diet-fed mice, as well as in palmitic acid (PA)-treated hepatocytes. Upregulation of hepatic TXNIP was p...
Source: Autophagy - November 16, 2020 Category: Cytology Authors: Park HS, Song JW, Park JH, Lim BK, Moon OS, Son HY, Lee JH, Gao B, Won YS, Kwon HJ Tags: Autophagy Source Type: research

Post translational modifications in Tuberculosis: Ubiquitination Paradox.
Abstract Innate immune signaling and xenophagy are crucial innate defense strategies exploited by the host to counteract intracellular pathogens with ubiquitination as a critical regulator of these processes. These pathogens, including Mycobacterium tuberculosis (M. tb), co-opt the host ubiquitin machinery by utilizing secreted or cell surface effectors to dampen innate host defenses. Inversely, the host utilizes ubiquitin ligase-mediated ubiquitination of intracellular pathogens and recruits autophagy receptors to induce xenophagy. In the current article, we discuss the co-option of the ubiquitin pathway by the M...
Source: Autophagy - November 15, 2020 Category: Cytology Authors: Shariq M, Quadir N, Sheikh JA, Singh AK, Bishai WR, Ehtesham NZ, Hasnain SE Tags: Autophagy Source Type: research

Protein complexes and neighborhoods driving autophagy.
Abstract Autophagy summarizes evolutionarily conserved, intracellular degradation processes targeting cytoplasmic material for lysosomal degradation. These encompass constitutive processes as well as stress responses, which are often found dysregulated in diseases. Autophagy pathways help in the clearance of damaged organelles, protein aggregates and macromolecules, mediating their recycling and maintaining cellular homeostasis. Protein-protein interaction networks contribute to autophagosome biogenesis, substrate loading, vesicular trafficking and fusion, protein translocations across membranes and degradation in...
Source: Autophagy - November 13, 2020 Category: Cytology Authors: Siva Sankar D, Dengjel J Tags: Autophagy Source Type: research

A VASt-domain protein regulates autophagy, membrane tension, and sterol homeostasis in rice blast fungus.
Abstract Sterols are a class of lipids critical for fundamental biological processes and membrane dynamics. These molecules are synthesized in the endoplasmic reticulum (ER) and are transported bi-directionally between the ER and plasma membrane (PM). However, the trafficking mechanism of sterols and their relationship with macroautophagy/autophagy are still poorly understood in the rice blast fungus Magnaporthe oryzae. Here, we identified the VAD1 Analog of StAR-related lipid transfer (VASt) domain-containing protein MoVast1 via co-immunoprecipitation in M. oryzae. Loss of MoVAST1 resulted in conidial defects, im...
Source: Autophagy - November 11, 2020 Category: Cytology Authors: Zhu XM, Li L, Cai YY, Wu XY, Shi HB, Liang S, Qu YM, Naqvi NI, Del Poeta M, Dong B, Lin FC, Liu XH Tags: Autophagy Source Type: research

Hydrogen peroxide mediates spermidine-induced autophagy to alleviate salt stress in cucumber.
In this study, we demonstrated that spermidine (Spd), a kind of polyamine, was involved in the regulation of salt tolerance through activating the expression of ATG (autophagy-related) genes and the formation of autophagosomes in cucumber under salt stress. Furthermore, NADPH oxidase-derived apoplastic H2O2-mediated Spd-induced salt tolerance and autophagy. Exogenous Spd significantly increased the tolerance to salt stress and inhibited the accumulation and ubiquitination of insoluble proteins. Foliar application of Spd promoted the transcript levels of ATG genes and autophagosomes formation. Besides, Spd induced the expre...
Source: Autophagy - November 10, 2020 Category: Cytology Authors: Zhang Y, Wang Y, Wen W, Shi Z, Gu Q, Ahammed GJ, Cao K, Shah Jahan M, Shu S, Wang J, Sun J, Guo S Tags: Autophagy Source Type: research

Equine lentivirus counteracts SAMHD1 restriction by Rev-mediated degradation of SAMHD1 via the BECN1-dependent lysosomal pathway.
Abstract The innate immune restriction factor SAMHD1 can inhibit diverse viruses in myeloid cells. Mechanistically, SAMHD1 inhibits lentiviral replication including HIV-1 by depleting the nucleotide pool to interfere with their reverse transcription. Equine infectious anemia virus (EIAV) is an ancient lentivirus that preferentially attacks macrophages. However, the mechanism by which EIAV successfully establishes infection in macrophages with functional SAMHD1 remains unclear. Here, we demonstrate that while equine SAMDH1 can limit EIAV replication in equine macrophages at the reverse transcription stage, the anti...
Source: Autophagy - November 10, 2020 Category: Cytology Authors: Ren H, Yin X, Su C, Guo M, Wang XF, Na L, Lin Y, Wang X Tags: Autophagy Source Type: research

ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota.
Abstract The orphan nuclear receptor ESRRA (estrogen related receptor alpha) is critical in mitochondrial biogenesis and macroautophagy/autophagy function; however, the roles of ESRRA in intestinal function remain uncharacterized. Herein we identified that ESRRA acts as a key regulator of intestinal homeostasis by amelioration of colonic inflammation through activation of autophagic flux and control of host gut microbiota. Esrra-deficient mice presented with increased susceptibility to dextran sodium sulfate (DSS)-induced colitis with upregulation of intestinal inflammation. In addition, esrra-null mice had depres...
Source: Autophagy - November 10, 2020 Category: Cytology Authors: Kim S, Lee JY, Shin SG, Kim JK, Silwal P, Kim YJ, Shin NR, Kim PS, Won M, Lee SH, Kim SY, Sasai M, Yamamoto M, Kim JM, Bae JW, Jo EK Tags: Autophagy Source Type: research

HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1.
Abstract Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing world health problem with a more favourable prognosis for patients with human papillomavirus (HPV)-positive tumors compared to those with HPV-negative OPSCC. How HPV confers a less aggressive phenotype, however, remains undefined. We demonstrated that HPV-positive OPSCC cells display reduced macroautophagy/autophagy activity, mediated by the ability of HPV-E7 to interact with AMBRA1, to compete with its binding to BECN1 and to trigger its calpain-dependent degradation. Moreover, we have shown that AMBRA1 downregulation and pharmacological inhi...
Source: Autophagy - November 10, 2020 Category: Cytology Authors: Antonioli M, Pagni B, Vescovo T, Ellis R, Cosway B, Rollo F, Bordoni V, Agrati C, Labus M, Covello R, Benevolo M, Ippolito G, Robinson M, Piacentini M, Lovat P, Fimia GM Tags: Autophagy Source Type: research

AMPK-induced autophagy as a key regulator of cell migration.
Abstract Cell migration is a highly dynamic and energy-intensive process that ensures the correct targeting of cells during embryonic and postnatal development. In recent work, we highlighted the importance of macroautophagy/autophagy in regulating the dynamics of cell migration under baseline conditions and in response to a diverse set of molecular factors. Genetic suppression of autophagy-related genes induced longer stationary phases in migrating cells and cell stalling at the beginning of the migratory stream. We also showed that autophagy is required for recycling of the focal adhesion molecule PXN (paxillin)...
Source: Autophagy - November 10, 2020 Category: Cytology Authors: Cedric B, Armen S Tags: Autophagy Source Type: research

Macrophage mitochondrial MFN2 (mitofusin 2) links immune stress and immune response through reactive oxygen species (ROS) production.
rzano A, Celada A Abstract MFN2 (mitofusin 2) is required for mitochondrial fusion and for mitochondria-endoplasmic reticulum interaction. Using myeloid-conditional KO mice models, we found that MFN2 but not MFN1 is a prerequisite for the adaptation of mitochondrial respiration to stress conditions as well as for the production of reactive oxygen species (ROS). The deficient ROS production in the absence of MFN2 impairs the induction of cytokines and nitric oxide, and is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. The lack of MFN2 in macrophages causes an impaired resp...
Source: Autophagy - November 10, 2020 Category: Cytology Authors: Lloberas J, Muñoz JP, Hernández-Álvarez MI, Cardona PJ, Zorzano A, Celada A Tags: Autophagy Source Type: research

Regulation and Function of Autophagy in Pancreatic Cancer.
Abstract Oncogenic KRAS mutation-driven pancreatic ductal adenocarcinoma is currently the fourth-leading cause of cancer-related deaths in the United States. Macroautophagy (hereafter "autophagy") is one of the lysosome-dependent degradation systems that can remove abnormal proteins, damaged organelles, or invading pathogens by activating dynamic membrane structures (e.g., phagophores, autophagosomes, and autolysosomes). Impaired autophagy (including excessive activation and defects) is a pathological feature of human diseases, including pancreatic cancer. However, dysfunctional autophagy has many types ...
Source: Autophagy - November 8, 2020 Category: Cytology Authors: Li J, Chen X, Kang R, Zeh H, Klionsky DJ, Tang D Tags: Autophagy Source Type: research

Measurement of autophagic flux in humans: an optimized method for blood samples.
In this study we detail a method whereby human macroautophagic/autophagic flux can be directly measured from human blood samples. We show that whole blood samples can be treated with the lysosomal inhibitor chloroquine, and peripheral blood mononuclear cells isolated from these samples could be used to measure autophagic machinery protein LC3B-II. Blocking of autophagic flux in cells while still in whole blood represents an important advance because it preserves genetic, nutritional, and signaling parameters inherent to the individual. We show this method was reproducible and defined LC3B-II as the best protein to measure ...
Source: Autophagy - November 8, 2020 Category: Cytology Authors: Bensalem J, Hattersley KJ, Hein LK, Tong Teong X, Carosi JM, Hassiotis S, Grose RH, Fourrier C, Heilbronn LK, Sargeant TJ Tags: Autophagy Source Type: research

C53 is a cross-kingdom conserved reticulophagy receptor that bridges the gap betweenselective autophagy and ribosome stalling at the endoplasmic reticulum.
Abstract Reticulophagy, the autophagic degradation of the endoplasmic reticulum, is crucial to maintain ER homeostasis during stress. Although several reticulophagy receptors have been discovered recently, most of them have been studied using nutrient starvation. How macroautophagy/autophagy cross-talks with other ER-quality control mechanisms is largely unknown. Using ATG8-based affinity proteomics in the model plant Arabidopsis thaliana, we identified AT5G06830/C53, a soluble protein that directly interacts with ATG8. Biochemical and biophysical characterization of C53-ATG8 interaction using both human (CDK5RAP3...
Source: Autophagy - November 8, 2020 Category: Cytology Authors: Stephani M, Picchianti L, Dagdas Y Tags: Autophagy Source Type: research

Atg11-mediated activation of Atg1 kinase in fission yeast.
Abstract The protein kinase Atg1 is a key player in macroautophagy/autophagy, but how its activity is regulated in various organisms is inadequately understood. Our recent study showed that in the fission yeast Schizosaccharomyces pombe, Atg1 kinase activity depends on Atg11, but not Atg13, Atg17, or Atg101. Notably, a 62 amino acid region of S. pombe Atg11 is sufficient for activating Atg1. This region is composed of two parts: an Atg1-binding domain and a homodimerization domain. Atg11 uses this region to dimerize Atg1. Dimerized Atg1 is activated through cis-autophosphorylation. PMID: 33164662 [PubMed - as...
Source: Autophagy - November 8, 2020 Category: Cytology Authors: Pan ZQ, Du LL Tags: Autophagy Source Type: research

Highlights in the fight against COVID-19: does autophagy play a role in SARS-CoV-2 infection?
Abstract In the preceding months, the novel SARS-CoV-2 pandemic has devastated global communities. The need for safe and effective prophylactic and therapeutic treatments to combat COVID-19 - the human disease resulting from SARS-CoV-2 infection - is clear. Here, we present recent developments in the effort to combat COVID-19 and consider whether SARS-CoV-2 may potentially interact with the host autophagy pathway. Abbreviations: ACE2, angiotensin converting enzyme II; βCoV, betacoronavirus; COVID-19, Coronavirus Disease 2019; CQ, chloroquine; DMV, double-membrane vesicle; GI, gastrointestinal; HCQ, hydroxychl...
Source: Autophagy - November 5, 2020 Category: Cytology Authors: Delorme-Axford E, Klionsky DJ Tags: Autophagy Source Type: research

Autophagy-independent function of lipidated LC3 essential for TFEB activation during the lysosomal damage responses.
Abstract Lysosomes are digestive organelles in cells containing many hydrolases, and also serve as a signaling hub to integrate intracellular and extracellular inputs; therefore, the integrity of lysosomes is critical for cellular homeostasis. Many agents and conditions can damage lysosomal membranes, which lead to leakage of lysosomal acidic contents into the cytosol thus becoming harmful for cells. Accordingly, cells have developed several defense systems to cope with damaged lysosomes, but underlying mechanisms of each system and their cross-talks are unclear. In our recent study, we found that a master transcr...
Source: Autophagy - November 5, 2020 Category: Cytology Authors: Nakamura S, Akayama S, Yoshimori T Tags: Autophagy Source Type: research

Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3.
Abstract Senile osteoporosis (OP) is often concomitant with decreased autophagic activity. OPTN (optineurin), a macroautophagy/autophagy (hereinafter referred to as autophagy) receptor, is found to play a pivotal role in selective autophagy, coupling autophagy with bone metabolism. However, its role in osteogenesis is still mysterious. Herein, we identified Optn as a critical molecule of cell fate decision for bone marrow mesenchymal stem cells (MSCs), whose expression decreased in aged mice. Aged mice revealed osteoporotic bone loss, elevated senescence of MSCs, decreased osteogenesis, and enhanced adipogenesis, ...
Source: Autophagy - November 4, 2020 Category: Cytology Authors: Liu ZZ, Hong CG, Hu WB, Chen ML, Duan R, Li HM, Yue T, Cao J, Wang ZX, Chen CY, Hu XK, Wu B, Liu HM, Tan YJ, Liu JH, Luo ZW, Zhang Y, Rao SS, Luo MJ, Yin H, Wang YY, Xia K, Xu L, Tang SY, Hu RG, Xie H Tags: Autophagy Source Type: research

Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein.
Abstract Macroautophagy/autophagy (hereafter autophagy), the process of mass degradation of unnecessary elements within the cell, is often dysregulated in many diseases such as cancer, atherosclerosis, and neurodegenerative diseases. Hence, autophagy modulating agents have a great potential to be therapeutic agents for the autophagy-related diseases. Here we report that an anti-depressant drug sertraline (Sert) is an autophagy-inducing agent. Mechanistically, Sert potentially binds to and antagonizes the mitochondrial VDAC1 (voltage dependent anion channel 1), resulting in reduced cellular ATP (adenosine triphosph...
Source: Autophagy - October 30, 2020 Category: Cytology Authors: Hwang HY, Shim JS, Kim D, Kwon HJ Tags: Autophagy Source Type: research

A novel reticulophagy receptor, Epr1: a bridge between the phagophore protein Atg8 and ER transmembrane VAP proteins.
Abstract Reticulophagy, a type of selective autophagy that specifically targets and degrades parts of the endoplasmic reticulum (ER) network (sheets or tubules), plays a crucial role in the responses to ER stress. The selectivity of the ER cargo recognition relies on the unique reticulophagy receptors, which tether and deliver cargos to phagophores, the precursors to autophagosomes. Various integral membrane proteins have been well characterized as reticulophagy receptors, including Atg39, Atg40, RETREG1/FAM134B, SEC62, RTN3L, CCPG1, TEX264, and ATL3, in both yeast and mammals in the past five years. In a recent p...
Source: Autophagy - October 29, 2020 Category: Cytology Authors: Yang Y, Klionsky DJ Tags: Autophagy Source Type: research

BECN2 (beclin 2)-mediated non-canonical autophagy in innate immune signaling and tumor development.
Abstract BECN2 (beclin 2) is a newly identified mammalian-specific macroautophagy/autophagy family member, and plays a critical role in the control of obesity and insulin sensitivity. However, its role in innate immune signaling and inflammation remains elusive. In our recent study, we show that BECN2 functions as a negative regulator in innate immune signaling and tumor development through non-canonical autophagy. Loss of Becn2 causes splenomegaly, lymphadenopathy, elevated proinflammatory cytokine production and spontaneous lymphoma development in mice. Mechanistically, BECN2 mediates the degradation of MAP3K7/T...
Source: Autophagy - October 29, 2020 Category: Cytology Authors: Zhu M, Deng G, Xing C, Nie G, Wang RF Tags: Autophagy Source Type: research

Extracellular SQSTM1 as an inflammatory mediator.
Abstract Excessive inflammation may lead to irreparable injury and even death, but the key mediators and underlying mechanisms remain unclear. Our recent findings indicate that SQSTM1/p62 (sequestosome 1), a well-known macroautophagy/autophagy receptor, is a lethal inflammatory mediator of sepsis and septic shock. The release of SQSTM1 occurs during tissue damage or microbial invasion through two main ways: one is passive and the other is active. Passive release occurs in the context of GSDMD-mediated pyroptosis. Active SQSTM1 secretion requires two basic steps: the first step is the expression and phosphorylation...
Source: Autophagy - October 28, 2020 Category: Cytology Authors: Zou B, Liu J, Klionsky DJ, Tang D, Kang R Tags: Autophagy Source Type: research

ATF4 links ER stress with reticulophagy in glioblastoma cells.
SJL Abstract Selective degradation of the endoplasmic reticulum (ER; reticulophagy) is a type of autophagy involved in the removal of ER fragments. So far, amino acid starvation as well as ER stress have been described as inducers of reticulophagy, which in turn restores cellular energy levels and ER homeostasis. Here, we explored the autophagy-inducing mechanisms that underlie the autophagic cell death (ACD)-triggering compound loperamide (LOP) in glioblastoma cells. Interestingly, LOP triggers upregulation of the transcription factor ATF4, which is accompanied by the induction of additional ER stress markers. No...
Source: Autophagy - October 28, 2020 Category: Cytology Authors: Zielke S, Kardo S, Zein L, Mari M, Covarrubias-Pinto A, Kinzler MN, Meyer N, Stolz A, Fulda S, Reggiori F, Kögel D, van Wijk SJL Tags: Autophagy Source Type: research

Ischemia-induced Upregulation of Autophagy Preludes Dysfunctional Lysosomal Storage and Associated Synaptic Impairments in Neurons.
This study investigated the effects of ischemic stress on autophagy and synaptic structures using a rat model of oxygen-glucose deprivation (OGD) in hippocampal neurons and a mouse model of middle cerebral artery occlusion (MCAO). Upon acute ischemia, an initial autophagy modification occurred in an upregulation manner. Following, the number of lysosomes increased, as well as lysosomal volume, indicating dysfunctional lysosomal storage. These changes were prevented by inhibiting autophagy via 3-methyladenine (3-MA) treatment or ATG7 (autophagy related 7) knockdown, or were mimicked by rapamycin (RAPA), a known activator of...
Source: Autophagy - October 28, 2020 Category: Cytology Authors: Zhang X, Wei M, Fan J, Yan W, Zha X, Song H, Wan R, Yin Y, Wang W Tags: Autophagy Source Type: research

Sensitive ELISA-based detection method for the mitophagy marker p-S65-Ub in human cells, autopsy brain, and blood samples.
Abstract Mitochondrial dysfunction is an early, imminent event in neurodegenerative disorders including Parkinson disease (PD) and Alzheimer disease (AD). The enzymatic pair PINK1 and PRKN/Parkin recognize and transiently label damaged mitochondria with ubiquitin (Ub) phosphorylated at Ser65 (p-S65-Ub) as a signal for degradation via the autophagy-lysosome system (mitophagy). Despite its discovery in cell culture several years ago, robust and quantitative detection of altered mitophagy in vivo has remained challenging. Here we developed a sandwich ELISA targeting p-S65-Ub with the goal to assess mitophagy levels i...
Source: Autophagy - October 28, 2020 Category: Cytology Authors: Watzlawik JO, Hou X, Truban D, Ramnarine C, Barodia SK, Gendron TF, Heckman MG, DeTure M, Siuda J, Wszolek ZK, Scherzer CR, Ross OA, Bu G, Dickson DW, Goldberg MS, Fiesel FC, Springer W Tags: Autophagy Source Type: research

Cp1/cathepsin L is required for autolysosomal clearance in Drosophila.
Abstract Macroautophagy/autophagy is a highly conserved lysosomal degradative pathway important for maintaining cellular homeostasis. Much of our current knowledge of autophagy is focused on the initiation steps in this process. Recently, an understanding of later steps, particularly lysosomal fusion leading to autolysosome formation and the subsequent role of lysosomal enzymes in degradation and recycling, is becoming evident. Autophagy can function in both cell survival and cell death, however, the mechanisms that distinguish adaptive/survival autophagy from autophagy-dependent cell death remain to be establishe...
Source: Autophagy - October 28, 2020 Category: Cytology Authors: Xu T, Nicolson S, Sandow JJ, Dayan S, Jiang X, Manning JA, Webb AI, Kumar S, Denton D Tags: Autophagy Source Type: research

PTPN9-mediated dephosphorylation of VTI1B promotes ATG16L1 precursor fusion and autophagosome formation.
Abstract Macroautophagy/autophagy is an evolutionarily conserved intracellular pathway for the degradation of cytoplasmic materials. Under stress conditions, autophagy is upregulated and double-membrane autophagosomes are formed by the expansion of phagophores. The ATG16L1 precursor fusion contributes to development of phagophore structures and is critical for the biogenesis of autophagosomes. Here, we discovered a novel role of the protein tyrosine phosphatase PTPN9 in the regulation of homotypic ATG16L1 vesicle fusion and early autophagosome formation. Depletion of PTPN9 and its Drosophila homolog Ptpmeg2 impair...
Source: Autophagy - October 28, 2020 Category: Cytology Authors: Chou HY, Lee YT, Lin YJ, Wen JK, Peng WH, Hsieh PL, Lin SY, Hung CC, Chen GC Tags: Autophagy Source Type: research

Autophagy under construction: insights from in vitro reconstitution of autophagosome nucleation.
Abstract Macroautophagy/autophagy is a complex process that involves over 40 proteins in Saccharomyces cerevisiae. How these proteins are organized, and their activities orchestrated to facilitate an efficient autophagic mechanism remain elusive. Sawa-Makarsha et al. reconstitute the initial steps of autophagosome biogenesis during selective autophagy using autophagy factors purified from yeast. Their results show that Atg9 vesicles serve as platforms for the recruitment of the autophagy machinery, and establish membrane contact sites to initiate lipid transfer for autophagosome biogenesis. Abbreviations: GUV, gia...
Source: Autophagy - October 23, 2020 Category: Cytology Authors: Metur SP, Klionsky DJ Tags: Autophagy Source Type: research

Mir214-3p and Hnf4a/Hnf4 α reciprocally regulate Ulk1 expression and autophagy in nonalcoholic hepatic steatosis.
Mir214-3p and Hnf4a/Hnf4α reciprocally regulate Ulk1 expression and autophagy in nonalcoholic hepatic steatosis. Autophagy. 2020 Oct 20;:1-17 Authors: Lee DH, Park SH, Ahn J, Hong SP, Lee E, Jang YJ, Ha TY, Huh YH, Ha SY, Jeon TI, Jung CH Abstract Macroautophagy/autophagy, a self-degradative process, regulates metabolic homeostasis in response to various stress conditions and is a therapeutic target for nonalcoholic fatty liver disease. We found that autophagic activity was inhibited as a result of a significant reduction in the expression of autophagy-related genes such as Ulk1 in a mouse model...
Source: Autophagy - October 20, 2020 Category: Cytology Authors: Lee DH, Park SH, Ahn J, Hong SP, Lee E, Jang YJ, Ha TY, Huh YH, Ha SY, Jeon TI, Jung CH Tags: Autophagy Source Type: research

Mammalian Atg8-family proteins are upstream regulators of the lysosomalsystem by controlling MTOR and TFEB.
In conclusion, mAtg8s, IRGM and STX17 control lysosomal biogenesis by their combined or individual effects on MTOR, TFEB, and PPP3/calcineurin, independently of their roles in the formation of autophagosomal membranes. PMID: 33070669 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - October 19, 2020 Category: Cytology Authors: Kumar S, Jain A, Choi SW, Peixoto Duarte da Silva G, Allers L, Mudd MH, Peters RS, Anonsen JH, Rusten TE, Lazarou M, Deretic V Tags: Autophagy Source Type: research

HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4+ T cell death.
Abstract The immunodeficiency observed in HIV-1-infected patients is mainly due to uninfected bystander CD4+ T lymphocyte cell death. The viral envelope glycoproteins (Env), expressed at the surface of infected cells, play a key role in this process. Env triggers macroautophagy/autophagy, a process necessary for subsequent apoptosis, and the production of reactive oxygen species (ROS) in bystander CD4+ T cells. Here, we demonstrate that Env-induced oxidative stress is responsible for their death by apoptosis. Moreover, we report that peroxisomes, organelles involved in the control of oxidative stress, are targeted...
Source: Autophagy - October 19, 2020 Category: Cytology Authors: Daussy CF, Galais M, Pradel B, Robert-Hebmann V, Sagnier S, Pattingre S, Biard-Piechaczyk M, Espert L Tags: Autophagy Source Type: research

Autophagy unleashes noncanonical microRNA functions.
S, Duchêne J, Megens RTA, Sattler M, Weber C Abstract MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression which act by guiding AGO (argonaute) proteins to target RNA transcripts in the RNA-induced silencing complex (RISC). This macromolecular complex includes multiple additional components (e.g., TNRC6A) that allow for interaction with enzymes mediating inhibition of translation or RNA decay. However, miRNAs also reside in low-molecular weight complexes without being engaged in target repression, and their function in this context is largely unknown. Our recent findings show that endot...
Source: Autophagy - October 15, 2020 Category: Cytology Authors: Santovito D, Egea V, Bidzhekov K, Natarelli L, Mourão A, Blanchet X, Wichapong K, Aslani M, Brunßen C, Horckmans M, Hristov M, Geerlof A, Lutgens E, Daemen MJAP, Hackeng T, Ries C, Chavakis T, Morawietz H, Naumann R, Hundelshausen PV, Steffens S, Duchê Tags: Autophagy Source Type: research

Caty Casas (1967-2020).
PMID: 33043766 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - October 12, 2020 Category: Cytology Authors: Boya P Tags: Autophagy Source Type: research

SMAD3 promotes autophagy dysregulation by triggering lysosome depletion in tubular epithelial cells in diabetic nephropathy.
In conclusion, SMAD3 promotes lysosome depletion via the inhibition of TFEB-dependent lysosome biogenesis; this may be an important mechanism underlying autophagy dysregulation in the progression of diabetic nephropathy. Abbreviations: AGEs: advanced glycation end products; ATP6V1H: ATPase H+ transporting V1 subunit H; CTSB: cathepsin B; ChIP: chromatin immunoprecipitation; Co-BSA: control bovine serum albumin; DN: diabetic nephropathy; ELISA: enzyme-linked immunosorbent assay; FN1: fibronectin 1; HAVCR1/TIM1/KIM-1: hepatitis A virus cellular receptor 1; LAMP1: lysosomal associated membrane protein 1; LMP: lysosome membran...
Source: Autophagy - October 12, 2020 Category: Cytology Authors: Yang C, Chen XC, Li ZH, Wu HL, Jing KP, Huang XR, Ye L, Wei B, Lan HY, Liu HF Tags: Autophagy Source Type: research

SSH1 impedes SQSTM1/p62 flux and MAPT/Tau clearance independent of CFL (cofilin) activation.
Abstract Accumulation of toxic protein assemblies and damaged mitochondria are key features of neurodegenerative diseases, which arise in large part from clearance defects in the Macroautophagy/autophagy-lysosome system. The autophagy cargo receptor SQSTM1/p62 plays a major role in the clearance of ubiquitinated cargo through Ser403 phosphorylation by multiple kinases. However, no phosphatase is known to physiologically dephosphorylate SQSTM1 on this activating residue. RNAi-mediated knockdown and overexpression experiments using genetically encoded fluorescent reporters and defined mutant constructs in cell lines...
Source: Autophagy - October 12, 2020 Category: Cytology Authors: Fang C, Woo JA, Liu T, Zhao X, Cazzaro S, Yan Y, Matlack J, Kee T, LePochat P, Kang DE Tags: Autophagy Source Type: research

BNIP3L/Nix-induced mitochondrial fission, mitophagy, and impaired myocyte glucose uptake are abrogated by PRKA/PKA phosphorylation.
Abstract Lipotoxicity is a form of cellular stress caused by the accumulation of lipids resulting in mitochondrial dysfunction and insulin resistance in muscle. Previously, we demonstrated that the mitophagy receptor BNIP3L/Nix is responsive to lipotoxicity and accumulates in response to a high-fat (HF) feeding. To provide a better understanding of this observation, we undertook gene expression array and shot-gun metabolomics studies in soleus muscle from rodents on an HF diet. Interestingly, we observed a modest reduction in several autophagy-related genes. Moreover, we observed alterations in the fatty acyl comp...
Source: Autophagy - October 12, 2020 Category: Cytology Authors: da Silva Rosa SC, Martens MD, Field JT, Nguyen L, Kereliuk SM, Hai Y, Chapman D, Diehl-Jones W, Aliani M, West AR, Thliveris J, Ghavami S, Rampitsch C, Dolinsky VW, Gordon JW Tags: Autophagy Source Type: research

Atg8-mediated super-assembly of Atg40 induces local ER remodeling in reticulophagy.
Abstract Reticulophagy (or ER-phagy) is a type of selective autophagy that targets the endoplasmic reticulum (ER). In the process of reticulophagy, part of the ER is fragmented and packed within autophagosomes. However, the underlying mechanism that induces this local remodeling of ER subdomains was poorly understood. Our recent study showed that in the budding yeast Saccharomyces cerevisiae the reticulophagy receptor Atg40 plays an important role in ER remodeling beyond its role as a tether between the ER and the phagophore [1]. Atg40 has an ability to generate positive membrane curvature through the reticulon-li...
Source: Autophagy - October 10, 2020 Category: Cytology Authors: Mochida K, Nakatogawa H Tags: Autophagy Source Type: research

Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs.
In conclusion, AMBRA1-ERLIN1 interaction within MAM raft-like microdomains appears to be pivotal in promoting the formation of autophagosomes. PMID: 33034545 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - October 9, 2020 Category: Cytology Authors: Manganelli V, Matarrese P, Antonioli M, Gambardella L, Vescovo T, Gretzmeier C, Longo A, Capozzi A, Recalchi S, Riitano G, Misasi R, Dengjel J, Malorni W, Fimia GM, Sorice M, Garofalo T Tags: Autophagy Source Type: research

Metformin rescues muscle function in BAG3 myofibrillar myopathy models.
Abstract Dominant de novo mutations in the co-chaperone BAG3 cause a severe form of myofibrillar myopathy, exhibiting progressive muscle weakness, muscle structural failure, and protein aggregation. To elucidate the mechanism of disease in, and identify therapies for, BAG3 myofibrillar myopathy, we generated two zebrafish models, one conditionally expressing BAG3P209L and one with a nonsense mutation in bag3. While transgenic BAG3P209L-expressing fish display protein aggregation, modeling the early phase of the disease, bag3 -/- fish exhibit exercise dependent fiber disintegration, and reduced swimming activity, c...
Source: Autophagy - October 8, 2020 Category: Cytology Authors: Ruparelia AA, McKaige EA, Williams C, Schulze KE, Fuchs M, Oorschot V, Lacene E, Meregalli M, Lee C, Serrano RJ, Baxter EC, Monro K, Torrente Y, Ramm G, Stojkovic T, Lavoie JN, Bryson-Richardson RJ Tags: Autophagy Source Type: research