Mice deficient in UXT exhibit retinitis pigmentosa-like features via aberrant autophagy activation.
Abstract UXT (ubiquitously expressed prefoldin like chaperone), a small chaperone-like protein, is widely expressed in diverse human and mouse tissues and is more abundant in retina and kidney. However, the functional characterization of UXT at tissue level was largely unknown. Here, we reported that mice deficient in UXT exhibited salient features of retinal degenerative disease, similar to retinitis pigmentosa. Conditional knockout (CKO) of Uxt led to retinal degeneration and pigmentation in mice retina along with significant alterations of retinitis pigmentosa-related genes, which indicated UXT might be associa...
Source: Autophagy - August 2, 2020 Category: Cytology Authors: Pan M, Yin Y, Wang X, Wang Q, Zhang L, Hu H, Wang C Tags: Autophagy Source Type: research
The CCNY (cyclin Y)-CDK16 kinase complex: a new regulator of autophagy downstream of AMPK.
r B PMID: 32723157 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - July 29, 2020 Category: Cytology Authors: Vervoorts J, Neumann D, Lüscher B Tags: Autophagy Source Type: research
BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains.
Abstract Mitophagy, the elimination of damaged mitochondria through autophagy, promotes neuronal survival in cerebral ischemia. Previous studies found deficient mitophagy in ischemic neurons, but the mechanisms are still largely unknown. We determined that BNIP3L/NIX, a mitophagy receptor, was degraded by proteasomes, which led to mitophagy deficiency in both ischemic neurons and brains. BNIP3L exists as a monomer and homodimer in mammalian cells, but the effects of homodimer and monomer on mitophagy are unclear. Site-specific mutations in the transmembrane domain of BNIP3L (S195A and G203A) only formed the BNIP3L...
Source: Autophagy - July 28, 2020 Category: Cytology Authors: Wu X, Zheng Y, Liu M, Li Y, Ma S, Tang W, Yan W, Cao M, Zheng W, Jiang L, Wu J, Han F, Qin Z, Fang L, Hu W, Chen Z, Zhang X Tags: Autophagy Source Type: research
BSN (bassoon) and PRKN/parkin in concert control presynaptic vesicle autophagy.
Abstract Maintaining the integrity and function of the presynaptic neurotransmitter release apparatus is a demanding process for a post-mitotic neuron; the mechanisms behind it are still unclear. BSN (bassoon), an active zone scaffolding protein, has been implicated in the control of presynaptic macroautophagy/autophagy, a process we recently showed depends on poly-ubiquitination of synaptic proteins. Moreover, loss of BSN was found to lead to smaller synaptic vesicle (SV) pools and younger pools of the SV protein SV2. Of note, the E3 ligase PRKN/parkin appears to be involved in BSN deficiency-related changes in a...
Source: Autophagy - July 27, 2020 Category: Cytology Authors: Montenegro-Venegas C, Annamneedi A, Hoffmann-Conaway S, Gundelfinger ED, Garner CC Tags: Autophagy Source Type: research
Glycogen: the missing link in neuronal autophagy?
Abstract Macroautophagy/autophagy is an intracellular degradative pathway that is often induced as a pro-survival process for cells under stress. A few recent reports establish the role of the glycogen metabolic pathway in neuronal cell survival in conditions such as oxidative stress and hypoxia, and the possible link between glycogen synthesis and autophagy induction. This commentary highlights the emerging role of GYS (glycogen synthase) in neuronal autophagy and stress response. PMID: 32718210 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - July 27, 2020 Category: Cytology Authors: Onkar A, Sheshadri D, Ganesh S Tags: Autophagy Source Type: research
NPC-phagy: selective autophagy of the nuclear pore complexes.
Abstract Selective autophagy is critical for the regulation of cellular homeostasis in organisms from yeast to humans. This process is a specific degradation pathway for a wide variety of substrates including unwanted cytosolic components, such as protein aggregates, damaged and/or superfluous organelles, and pathogens. However, it has been less clear as to whether a protein complex or substructure of an organelle can be targeted for removal by selective autophagy. One example of such a substrate is the nuclear pore complex (NPC), a large macromolecular assembly that is present throughout the nuclear envelope. Her...
Source: Autophagy - July 27, 2020 Category: Cytology Authors: Yin Z, Klionsky DJ Tags: Autophagy Source Type: research
Chloroquine in fighting COVID-19: good, bad, or both?
Abstract Coronavirus disease 2019 (COVID-19) has attracted worldwide attention due to its speed of progression and elevated mortality rate. Amid the rush to develop treatments, recent hopes have focused on the anti-malarial drug chloroquine or the derivative hydroxychloroquine. Here, we briefly discuss the evidence for the potential use of these drugs with regard to the current pandemic. PMID: 32713288 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - July 25, 2020 Category: Cytology Authors: Tang D, Li J, Zhang R, Kang R, Klionsky DJ Tags: Autophagy Source Type: research
PtdIns4P restriction by hydrolase SAC1 decides specific fusion of autophagosomes with lysosomes.
Abstract Biogenesis of autophagosomes is the early step of macroautophagy/autophagy and requires membrane acquisition mainly from ER-Golgi-sourced precursor vesicles. Matured autophagosomes fuse with lysosomes for final degradation. However, how this selective fusion is determined remains elusive. Here, we identified Sac1 by a high throughput screen in Saccharomyces cerevisiae to show it was critical for autophagosome-lysosome fusion through its PtdIns4P phosphatase activity. Sac1 deficiency caused a dramatic increase of PtdIns4P at early Golgi apparatus and abnormal incorporation of PtdIns4P into Atg9 vesicles an...
Source: Autophagy - July 21, 2020 Category: Cytology Authors: Zhang H, Zhou J, Xiao P, Lin Y, Gong X, Liu S, Xu Q, Wang M, Ren H, Lu M, Wang Y, Zhu J, Xie Z, Li H, Lu K Tags: Autophagy Source Type: research
CALCOCO1 is a soluble reticulophagy receptor.
Abstract The endoplasmic reticulum (ER) is the largest membrane-bound organelle in eukaryotic cells and plays critical roles in diverse processes in metabolism, signaling and intracellular organization. In response to stress stimuli such as nutrient deprivation, accumulation of misfolded proteins or exposure to chemicals, the ER increases in size through upregulated synthesis of its components to counteract the stress. To restore physiological size, the excess ER components are continuously dismantled and degraded by reticulophagy, a form of autophagy that targets, via adaptor molecules called reticulophagy recept...
Source: Autophagy - July 20, 2020 Category: Cytology Authors: Nthiga TM, Shrestha BK, Lamark T, Johansen T Tags: Autophagy Source Type: research
Ramping up the autophagy-lysosome system to cope with osmotic stress.
T, Haucke V Abstract Osmotic stress is a critical challenge for mammalian cells as loss of water triggered by a hyperosmotic environment promotes harmful protein aggregation and impairs cell survival. How the degradative capacity of cells, in particular the macroautophagy/autophagy-lysosome system, is adapted to meet the proteolytic demands induced by osmotic challenge remains poorly understood. We have identified a hitherto unknown pathway that is activated by hyperosmotic stress and serves to link alterations in cellular ion homeostasis to the induction of autophagy and lysosomal gene expression and, thereby, to...
Source: Autophagy - July 20, 2020 Category: Cytology Authors: López-Hernández T, Maritzen T, Haucke V Tags: Autophagy Source Type: research
Hepatic Peroxisomal β-Oxidation Suppresses Lipophagy via RPTOR Acetylation and MTOR Activation.
Hepatic Peroxisomal β-Oxidation Suppresses Lipophagy via RPTOR Acetylation and MTOR Activation. Autophagy. 2020 Jul 20;: Authors: He A, Dean JM, Lu D, Chen Y, Lodhi IJ Abstract Hepatic lipid homeostasis is controlled by a coordinated regulation of various metabolic pathways involved in de novo synthesis, uptake, storage, and catabolism of lipids. Disruption of this balance could lead to hepatic steatosis. Peroxisomes play an essential role in lipid metabolism, yet their importance is often overlooked. In a recent study, we demonstrated a role for hepatic peroxisomal β-oxidation in autophagic...
Source: Autophagy - July 20, 2020 Category: Cytology Authors: He A, Dean JM, Lu D, Chen Y, Lodhi IJ Tags: Autophagy Source Type: research
Autophagy in farm animals: current knowledge and future challenges.
AUTOPHAGY IN FARM ANIMALS: CURRENT KNOWLEDGE AND FUTURE CHALLENGES. Autophagy. 2020 Jul 18;: Authors: Tesseraud S, Avril P, Bonnet M, Bonnieu A, Cassar-Malek I, Chabi B, Dessauge F, Gabillard JC, Perruchot MH, Seiliez I Abstract Autophagy (a process of cellular self-eating) is a conserved cellular degradative process that plays important roles in maintaining homeostasis and preventing nutritional, metabolic, and infection-mediated stresses. Surprisingly, little attention has been paid to the role of this cellular function in species of agronomical interest, and the details of how autophagy functions i...
Source: Autophagy - July 18, 2020 Category: Cytology Authors: Tesseraud S, Avril P, Bonnet M, Bonnieu A, Cassar-Malek I, Chabi B, Dessauge F, Gabillard JC, Perruchot MH, Seiliez I Tags: Autophagy Source Type: research
A nuclear role for Atg8-family proteins.
Abstract Despite the growing evidence that the macroautophagy/autophagy-related protein LC3 is localized in the nucleus, why and how it is targeted to the nucleus are poorly understood. In our recent study, we found that transcription factor seq (sequoia) interacts via its LIR motif with Atg8a, the Drosophila homolog of LC3, to negatively regulate the transcription of autophagy genes. Atg8a was found to also interact with the nuclear acetyltransferase complex subunit YL-1 and deacetylase Sirt2. Modulation of the acetylation status of Atg8a by YL-1 and Sirt2 affects the interaction between seq and Atg8a, and contro...
Source: Autophagy - July 18, 2020 Category: Cytology Authors: Jacomin AC, Petridi S, Di Monaco M, Nezis IP Tags: Autophagy Source Type: research
The interplay between PRKCI/PKC λ/ι, SQSTM1/p62, and autophagy orchestrates the oxidative metabolic response that drives liver cancer.
The interplay between PRKCI/PKCλ/ι, SQSTM1/p62, and autophagy orchestrates the oxidative metabolic response that drives liver cancer. Autophagy. 2020 Jul 18;: Authors: Moscat J, Diaz-Meco MT Abstract Hepatocellular carcinoma (HCC) is the consequence of chronic liver damage caused by the excessive generation of reactive oxygen species (ROS). To mitigate the deleterious effects of ROS, cells activate the transcription factor NFE2L2/NRF2, which is constitutively degraded through its partner KEAP1. The inactivation of KEAP1 by ROS results in the upregulation of NFE2L2, which leads to the upreg...
Source: Autophagy - July 18, 2020 Category: Cytology Authors: Moscat J, Diaz-Meco MT Tags: Autophagy Source Type: research
SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation.
ey JL Abstract SETX (senataxin) is an RNA/DNA helicase that has been implicated in transcriptional regulation and the DNA damage response through resolution of R-loop structures. Mutations in SETX result in either of two distinct neurodegenerative disorders. SETX dominant mutations result in a juvenile form of amyotrophic lateral sclerosis (ALS) called ALS4, whereas recessive mutations are responsible for ataxia called ataxia with oculomotor apraxia type 2 (AOA2). How mutations in the same protein can lead to different phenotypes is still unclear. To elucidate AOA2 disease mechanisms, we first examined gene expres...
Source: Autophagy - July 18, 2020 Category: Cytology Authors: Richard P, Feng S, Tsai YL, Li W, Rinchetti P, Muhith U, Irizarry-Cole J, Stolz K, Sanz LA, Hartono S, Hoque M, Tadesse S, Seitz H, Lotti F, Hirano M, Chédin F, Tian B, Manley JL Tags: Autophagy Source Type: research
Is it the time of autophagy fine-tuners for neuroprotection?
sas C Abstract Cells and organisms are intrinsically prepared to effectively deal with damage caused by insults and heal themselves by triggering a plethora of stress responses including macroautophagy/autophagy. However, autophagy may become malfunctional during aging, neurodegeneration, and neurotrauma. We aimed to overcome autophagy dysfunction by refining therapeutics using multi-target approaches. Thus, we have demonstrated that modulation of autophagy with the multitarget drug NeuroHeal is neuroprotective in several neurodegeneration models in which previous autophagy modulators have failed. The key element ...
Source: Autophagy - July 17, 2020 Category: Cytology Authors: Romeo-Guitart D, Marmolejo-Martínez-Artesero S, Casas C Tags: Autophagy Source Type: research
Autophagy core protein ATG5 is required for elongating spermatid development, sperm individualization and normal fertility in male mice.
Abstract Spermiogenesis is the longest phase of spermatogenesis, with dramatic morphological changes and a final step of spermiation, which involves protein degradation and the removal of excess cytoplasm; therefore, we hypothesized that macroautophagy/autophagy might be involved in the process. To test this hypothesis, we examined the function of ATG5, a core autophagy protein in male germ cell development. Floxed Atg5 and Stra8- iCre mice were crossed to conditionally inactivate Atg5 in male germ cells. In Atg5flox/flox; Stra8- iCre mutant mice, testicular expression of the autophagosome marker LC3A/B-...
Source: Autophagy - July 17, 2020 Category: Cytology Authors: Huang Q, Liu Y, Zhang S, Yap YT, Li W, Zhang D, Gardner A, Zhang L, Song S, Hess RA, Zhang Z Tags: Autophagy Source Type: research
MIR106A-5p upregulation suppresses autophagy and accelerates malignant phenotype in nasopharyngeal carcinoma.
Abstract Dysregulated microRNAs (miRNAs) are involved in carcinoma progression, metastasis, and poor prognosis. We demonstrated that in nasopharyngeal carcinoma (NPC), transactivated MIR106A-5p promotes a malignant phenotype by functioning as a macroautophagy/autophagy suppressor by targeting BTG3 (BTG anti-proliferation factor 3) and activating autophagy-regulating MAPK signaling. MIR106A-5p expression was markedly increased in NPC cases based on quantitative real-time PCR, miRNA microarray, and TCGA database analysis findings. Moreover, MIR106A-5p was correlated with advanced stage, recurrence, and poor clinical...
Source: Autophagy - July 5, 2020 Category: Cytology Authors: Zhu Q, Zhang Q, Gu M, Zhang K, Xia T, Zhang S, Chen W, Yin H, Yao H, Fan Y, Pan S, Xie H, Liu H, Cheng T, Zhang P, Zhang T, You B, You Y Tags: Autophagy Source Type: research
Regulation and repurposing of nutrient sensing and autophagy in innate immunity.
Abstract Nutrients not only act as building blocks but also as signaling molecules. Nutrient-availability promotes cell growth and proliferation and suppresses catabolic processes, such as macroautophagy/autophagy. These effects are mediated by checkpoint kinases such as MTOR (mechanistic target of rapamycin kinase), which is activated by amino acids and growth factors, and AMP-activated protein kinase (AMPK), which is activated by low levels of glucose or ATP. These kinases have wide-ranging activities that can be co-opted by immune cells upon exposure to danger signals, cytokines or pathogens. Here, we discuss r...
Source: Autophagy - July 5, 2020 Category: Cytology Authors: Sanchez-Garrido J, Shenoy AR Tags: Autophagy Source Type: research
Selective autophagy inhibition through disruption of the PIK3C3-containing complex I.
Abstract The PIK3C3/VPS34-containing phosphatidylinositol 3-kinase (PtdIns3K) initiation complex (complex I) is necessary for macroautophagy/autophagy initiation and is comprised of PIK3R4/VPS15-PIK3C3/VPS34-BECN1-ATG14, while the endosomal trafficking complex (complex II) is necessary for vesicle trafficking and is comprised of PIK3R4/VPS15-PIK3C3/VPS34-BECN1-UVRAG. This composition difference was exploited to identify novel and specific autophagy inhibitors that disrupted the BECN1-ATG14 protein-protein interaction, without affecting vesicle trafficking. A cellular NanoBRET assay was implemented to identify thes...
Source: Autophagy - July 3, 2020 Category: Cytology Authors: Pavlinov I, Salkovski M, Aldrich LN Tags: Autophagy Source Type: research
The Unfolded Protein Response Regulates Hepatic Autophagy by sXBP1-mediated Activation of TFEB.
Abstract Defective macroautophagy/autophagy and a failure to initiate the adaptive unfolded protein response (UPR) in response to the endoplasmic reticulum (ER) stress contributes to obesity-associated metabolic dysfunction. However, whether and how unresolved ER stress leads to defects in the autophagy pathway and to the progression of obesity-associated hepatic pathologies remains unclear. Obesity suppresses the expression of hepatic spliced XBP1 (X-box binding protein 1; sXBP1), the key transcription factor that promotes the adaptive UPR. Our RNA-seq analysis revealed that sXBP1 regulates genes involved in lyso...
Source: Autophagy - June 28, 2020 Category: Cytology Authors: Zhang Z, Qian Q, Li M, Shao F, Ding WX, Lira VA, Chen SX, Sebag SC, Hotamisligil GS, Cao H, Yang L Tags: Autophagy Source Type: research
A RILP-regulated pathway coordinating autophagosome biogenesis with transport.
Abstract Mammalian cells, including neurons, use macroautophagy (here 'autophagy') to degrade damaged proteins and organelles, and recycle nutrients in response to starvation and other forms of cell stress. The basic cellular machinery responsible for autophagy is highly conserved from yeast to mammals. However, evidence for specific adaptations to more complex organisms and in highly differentiated cells (e. g. neurons) remains limited. RILP (Rab interacting lysosomal protein) mediates retrograde transport of late endosomes (LEs) in nonneuronal mammalian cells. We have now found that RILP plays additional importa...
Source: Autophagy - June 28, 2020 Category: Cytology Authors: Khobrekar NV, Vallee RB Tags: Autophagy Source Type: research
AMPK is activated during lysosomal damage via a galectin-ubiquitin signal transduction system.
Abstract Lysosomal damage activates AMPK, a regulator of macroautophagy/autophagy and metabolism, and elicits a strong ubiquitination response. Here we show that the cytosolic lectin LGALS9 detects lysosomal membrane breach by binding to lumenal glycoepitopes, and directs both the ubiquitination response and AMPK activation. Proteomic analyses have revealed increased LGALS9 association with lysosomes, and concomitant changes in LGALS9 interactions with its newly identified partners that control ubiquitination-deubiquitination processes. An LGALS9-inetractor, deubiquitinase USP9X, dissociates from damaged lysosomes...
Source: Autophagy - June 28, 2020 Category: Cytology Authors: Jia J, Bissa B, Brecht L, Allers L, Choi SW, Gu Y, Zbinden M, Burge MR, Timmins G, Hallows K, Behrends C, Deretic V Tags: Autophagy Source Type: research
Photodynamic therapy: autophagy and mitophagy, apoptosis and paraptosis.
Abstract Macroautophagy/autophagy can play a cytoprotective role after photodynamic damage to malignant cells, depending on the site of subcellular damage initiated by reactive oxygen species. There is evidence for such protection when mitochondria are among the targets. Targeting lysosomes has been reported to be more effective for photokilling, perhaps because autophagy offers no cytoprotection. Photodynamic damage to both lysosomes and mitochondria can, however, markedly enhance the overall level of photokilling. Two mechanisms have been proposed to account for this result. Lysosomal photodamage leads to the re...
Source: Autophagy - June 25, 2020 Category: Cytology Authors: Kessel D, Reiners JJ Tags: Autophagy Source Type: research
Autophagy/virophagy: a "disposal strategy" to combat COVID-19.
Autophagy/virophagy: a "disposal strategy" to combat COVID-19. Autophagy. 2020 Jun 24;:1-2 Authors: Mijaljica D, Klionsky DJ Abstract Given the devastating consequences of the current COVID-19 pandemic and its impact on all of us, the question arises as to whether manipulating the cellular degradation (recycling, waste disposal) mechanism known as macroautophagy/autophagy (in particular, the selective degradation of virus particles, termed virophagy) might be a beneficial approach to fight the novel coronavirus, SARS-CoV-2. Knowing that "autophagy can reprocess everything", it seem...
Source: Autophagy - June 24, 2020 Category: Cytology Authors: Mijaljica D, Klionsky DJ Tags: Autophagy Source Type: research
Regulating RIPK1: another way in which ULK1 contributes to survival.
Abstract The mammalian ULK1 is the central initiating kinase of bulk and selective macroautophagy/autophagy processes. In the past, both autophagy-relevant and non-autophagy-relevant substrates of this Ser/Thr kinase have been reported. Here, we describe our recent finding that ULK1 also regulates TNF signaling pathways. We find that inhibition of autophagy or specifically ULK1 increases TNF-induced cell death. This autophagy-independent pro-survival function of ULK1 is mediated via the phosphorylation of RIPK1 at Ser357. RIPK1 is the central mediator of pro-inflammatory or pro-death signaling pathways induced by ...
Source: Autophagy - June 24, 2020 Category: Cytology Authors: Wu W, Stork B Tags: Autophagy Source Type: research
Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability.
Abstract Lysosomes, as primary degradative organelles, are the endpoint of different converging pathways, including macroautophagy. To date, lysosome degradative function has been mainly studied in interphase cells, while their role during mitosis remains controversial. Mitosis dictates the faithful transmission of genetic material among generations, and perturbations of mitotic division lead to chromosomal instability, a hallmark of cancer. Heretofore, correct mitotic progression relies on the orchestrated degradation of mitotic factors, which was mainly attributed to ubiquitin-triggered proteasome-dependent degr...
Source: Autophagy - June 23, 2020 Category: Cytology Authors: Almacellas E, Pelletier J, Day C, Ambrosio S, Tauler A, Mauvezin C Tags: Autophagy Source Type: research
RETREG1/FAM134B mediated autophagosomal degradation of AMFR/GP78 and OPA1 -a dual organellar turnover mechanism.
Abstract Turnover of cellular organelles, including endoplasmic reticulum (ER) and mitochondria, is orchestrated by an efficient cellular surveillance system. We have identified a mechanism for dual regulation of ER and mitochondria under stress. It is known that AMFR, an ER E3 ligase and ER-associated degradation (ERAD) regulator, degrades outer mitochondrial membrane (OMM) proteins, MFNs (mitofusins), via the proteasome and triggers mitophagy. We show that destabilized mitochondria are almost devoid of the OMM and generate "mitoplasts". This brings the inner mitochondrial membrane (IMM) in the proximit...
Source: Autophagy - June 19, 2020 Category: Cytology Authors: Mookherjee D, Das S, Mukherjee R, Bera M, Jana SC, Chakrabarti S, Chakrabarti O Tags: Autophagy Source Type: research
Neutrophils use selective autophagy receptor Sqstm1/p62 to target Staphylococcus aureus for degradation in vivo in zebrafish.
Abstract Macroautophagy/autophagy functions to degrade cellular components and intracellular pathogens. Autophagy receptors, including SQSTM1/p62, target intracellular pathogens. Staphylococcus aureus is a significant pathogen of humans, especially in immunocompromise. S. aureus may use neutrophils as a proliferative niche, but their intracellular fate following phagocytosis has not been analyzed in vivo. In vitro, SQSTM1 can colocalize with intracellular Staphylococcus aureus, but whether SQSTM1 is beneficial or detrimental in host defense against S. aureus in vivo is unknown. Here we determine the fate and locat...
Source: Autophagy - June 19, 2020 Category: Cytology Authors: Gibson JF, Prajsnar TK, Hill CJ, Tooke AK, Serba JJ, Tonge RD, Foster SJ, Grierson AJ, Ingham PW, Renshaw SA, Johnston SA Tags: Autophagy Source Type: research
Differential activation of eMI by distinct forms of cellular stress.
Abstract As one of the major, highly conserved catabolic pathways, autophagy delivers cytosolic components to lysosomes for degradation. It is essential for development, cellular homeostasis, and coping with stress. Reduced autophagy increases susceptibility to protein aggregation diseases and leads to phenotypes associated with aging. Of the three major forms of autophagy, macroautophagy (MA) can degrade organelles or aggregated proteins, and chaperone-mediated autophagy is specific for soluble proteins containing KFERQ-related targeting motifs. During endosomal microautophagy (eMI), cytoplasmic proteins are engu...
Source: Autophagy - June 19, 2020 Category: Cytology Authors: Mesquita A, Glenn J, Jenny A Tags: Autophagy Source Type: research
LUBAC and OTULIN regulate autophagy initiation and maturation by mediating the linear ubiquitination and the stabilization of ATG13.
In this study, we found an E3 ubiquitin ligase complex, linear ubiquitin chain assembly complex (LUBAC) and a de-ubiquitinating enzyme (DUB) OTULIN localize to the phagophore area to control autophagy initiation and maturation. LUBAC key component RNF31/HOIP translocates to the LC3 puncta area when autophagy is induced. RNF31 knockdown inhibits autophagy initiation, and cells are more sensitive to bacterial infection. OTULIN knockdown, however, promotes autophagy initiation but blocks autophagy maturation. In OTULIN knockdown cells, excessive ubiquitinated ATG13 protein was recruited to the phagophore for prolonged expansi...
Source: Autophagy - June 16, 2020 Category: Cytology Authors: Chu Y, Kang Y, Yan C, Yang C, Zhang T, Huo H, Liu Y Tags: Autophagy Source Type: research
PKD2/polycystin-2 induces autophagy by forming a complex with BECN1.
, Criollo A Abstract Macroautophagy/autophagy is an intracellular process involved in the breakdown of macromolecules and organelles. Recent studies have shown that PKD2/PC2/TRPP2 (polycystin 2, transient receptor potential cation channel), a non-selective cation channel permeable to Ca2+ that belongs to the family of transient receptor potential channels, is required for autophagy in multiple cell types by a mechanism that remains unclear. Here, we report that PKD2 forms a protein complex with BECN1 (beclin 1), a key protein required for the formation of autophagic vacuoles, by acting as a scaffold that interacts...
Source: Autophagy - June 16, 2020 Category: Cytology Authors: Peña-Oyarzun D, Rodriguez-Peña M, Burgos-Bravo F, Vergara A, Kretschmar C, Sotomayor-Flores C, Ramirez-Sarmiento CA, de Smedt H, Reyes M, Perez W, Torres VA, Morselli E, Altamirano F, Wilson CAM, Hill JA, Lavandero S, Criollo A Tags: Autophagy Source Type: research
NRBF2 is a RAB7 effector required for autophagosome maturation and mediates the association of APP-CTFs with active form of RAB7 for degradation.
In this study, we revealed an unknown mechanism by which NRBF2 modulates autophagosome maturation and APP-C-terminal fragment (CTF) degradation. Our data showed that NRBF2 localized at autolysosomes, and loss of NRBF2 impaired autophagosome maturation. Mechanistically, NRBF2 colocalizes with RAB7 and is required for generation of GTP-bound RAB7 by interacting with RAB7 GEF CCZ1-MON1A and maintaining the GEF activity. Specifically, NRBF2 regulates CCZ1-MON1A interaction with PI3KC3/VPS34 and CCZ1-associated PI3KC3 kinase activity, which are required for CCZ1-MON1A GEF activity. Finally, we showed that NRBF2 is involved...
Source: Autophagy - June 16, 2020 Category: Cytology Authors: Cai CZ, Yang C, Zhuang XX, Yuan NN, Wu MY, Tan JQ, Song JX, Cheung KH, Su H, Wang YT, Tang BS, Behrends C, Durairajan SSK, Yue Z, Li M, Lu JH Tags: Autophagy Source Type: research
Autophagy as an on-ramp to scientific discovery.
Abstract The common view of art and science as polar opposites along the educational spectrum can sometimes mask the degree to which they inform one another. In fact, art can also serve as a way to foster interest in querying the natural world, ultimately allowing us to recruit highly creative individuals to join the scientific community. We have experienced firsthand how cellular processes, such as autophagy, which are not usually highlighted or described in detail in foundational cell biology textbooks, have served as an on-ramp for artists at the undergraduate and high school levels in the context of scientific...
Source: Autophagy - June 16, 2020 Category: Cytology Authors: Garr C, M Sturgeon C, Franks N, A Segarra V Tags: Autophagy Source Type: research
Involvement of phosphorylation of ULK1 in alternative autophagy.
Abstract Alternative autophagy is an ATG5 (autophagy related 5)-independent, Golgi membrane-derived form of macroautophagy. ULK1 (unc-51 like kinase 1) is an essential initiator not only for canonical autophagy but also for alternative autophagy. However, the mechanism as to how ULK1 differentially regulates both types of autophagy has remained unclear. Recently, we identified a novel phosphorylation site of ULK1 at Ser746, which is required for alternative autophagy, but not canonical autophagy. We also identify RIPK3 (receptor-interacting serine-threonine kinase 3) as the kinase responsible for genotoxic stress-...
Source: Autophagy - June 16, 2020 Category: Cytology Authors: Torii S, Shimizu S Tags: Autophagy Source Type: research
Scission, a critical step in autophagosome formation.
Abstract A key feature of macroautophagy (hereafter autophagy) is the formation of the phagophore, a double-membrane compartment sequestering cargos and finally maturing into a vesicle termed an autophagosome; however, where these membranes originate from is not clear. In a previous study, researchers from the Rubinsztein lab proposed a model in which the autophagosome can evolve from the RAB11A-positive recycling endosome. In their recent paper, they determine that DNM2 (dynamin 2) functions in scission of the recycling endosome, and the release of the autophagosome precursor. These findings explain how the centr...
Source: Autophagy - June 16, 2020 Category: Cytology Authors: Lei Y, Klionsky DJ Tags: Autophagy Source Type: research
Triethylenetetramine (trientine): a caloric restriction mimetic with a new mode of action.
Abstract Caloric restriction mimetics (CRMs) are nontoxic macroautophagy/autophagy enhancers that act through the stimulation of cytoplasmic protein deacetylation reactions. Thus far, three functional classes of CRMs have been described: inhibitors of acetyltransferases (such as spermidine), inhibitors of acetyl coenzyme (AcCoA) synthesis (such as hydroxycitrate) and activators of deacetylases/sirtuins (such as resveratrol). Triethylenetetramine (also called trientine, abbreviated TETA) is a synthetic polyamine with resemblance in its structure to spermidine, a natural polyamine reputed for its pro-autophagic, ant...
Source: Autophagy - June 16, 2020 Category: Cytology Authors: Pietrocola F, Castoldi F, Madeo F, Kroemer G Tags: Autophagy Source Type: research
Phosphorylation of ULK1 serine 746 dictates ATG5-independent autophagy.
Abstract There is a type of noncanonical autophagy, which is independent of ATG5 (autophagy related 5), also referred to as alternative autophagy. Both canonical and ATG5-independent alternative autophagy require the initiator ULK1 (unc-51 like kinase 1), but how ULK1 regulates these two types of autophagy differently remains unclear. A recent paper from Torii et al. demonstrates that phosphorylation of ULK1 at Ser746 by RIPK3 (receptor interacting serine/threonine kinase 3) is the key difference between these two types of autophagy; this phosphorylation is exclusively found during alternative autophagy. PMID...
Source: Autophagy - June 16, 2020 Category: Cytology Authors: Wen X, Klionsky DJ Tags: Autophagy Source Type: research
Eicosapentaenoic acid attenuates renal lipotoxicity by restoring autophagic flux.
In conclusion, EPA counteracts lipotoxicity in the proximal tubule by alleviating autophagic numbness, making it potentially suitable as a novel treatment for obesity-related kidney diseases. PMID: 32546086 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - June 16, 2020 Category: Cytology Authors: Yamamoto T, Takabatake Y, Minami S, Sakai S, Fujimura R, Takahashi A, Namba-Hamano T, Matsuda J, Kimura T, Matsui I, Kaimori JY, Takeda H, Takahashi M, Izumi Y, Bamba T, Matsusaka T, Niimura F, Yanagita M, Isaka Y Tags: Autophagy Source Type: research
Autophagy as an emerging target for COVID-19: lessons from an old friend, chloroquine.
Abstract During the last week of December 2019, Wuhan (China) was confronted with the first case of respiratory tract disease 2019 (coronavirus disease 2019, COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the rapid outbreak of the transmission (~3.64 million positive cases and high mortality as of May 5, 2020), the world is looking for immediate and better therapeutic options. Still, much information is not known, including origin of the disease, complete genomic characterization, mechanism of transmission dynamics, extent of spread, possible genetic predisposition, clinic...
Source: Autophagy - June 10, 2020 Category: Cytology Authors: Bonam SR, Muller S, Bayry J, Klionsky DJ Tags: Autophagy Source Type: research
The C9orf72-SMCR8-WDR41 complex is a GAP for small GTPases.
We reported the cryo-electron microscopy (cryo-EM) structure of the C9orf72-SMCR8-WDR41 complex (CSW complex), unveiling that the CSW complex is a dimer of heterotrimers. Intriguingly, in the heterotrimer of the C9orf72-SMCR8-WDR41, C9orf72 interacts with SMCR8 in a manner similar to the FLNC-FNIP2 complex. Nevertheless, WDR41 is connected to the DENN domain of SMCR8 through its N-terminal β-strand and C-terminal helix but does not directly interact with C9orf72. Notably, the C9orf72-SMCR8 complex was demonstrated to act as a GAP for RAB8A and RAB11A in vitro. PMID: 32521185 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - June 10, 2020 Category: Cytology Authors: Tang D, Sheng J, Xu L, Yan C, Qi S Tags: Autophagy Source Type: research
Protein translocation into the ERGIC: an upstream event of secretory autophagy.
Abstract Macroautophagy/autophagy was recently shown to regulate unconventional protein secretion through a process called secretory autophagy. How the secretory cargo selectively enters into the secretory autophagosome has been a central question. Our recent studies indicate that cargo translocation into the ER-Golgi intermediate compartment, a compartment contributing membranes to the forming autophagosome, acts as a mechanism for secretory cargo entry into the vesicle and may be an early step for secretory autophagy. PMID: 32521187 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - June 10, 2020 Category: Cytology Authors: Liu L, Zhang M, Ge L Tags: Autophagy Source Type: research
Open questions for harnessing autophagy-modulating drugs in the SARS-CoV-2 war: Hope or Hype?
Abstract At a time when the world faces an emotional breakdown, crushing our dreams, if not, taking our lives, we realize that together we must fight the war against the COVID-19 outbreak even if almost the majority of the scientific community finds itself confined at home. Every day, we, scientists, listen to the latest news with its promises and announcements. Across the world, a surge of clinical trials trying to cure or slow down the coronavirus pandemic has been launched to bring hope instead of fear and despair. One first proposed clinical trial has drawn worldwide hype to the benefit of chloroquine (CQ), in...
Source: Autophagy - June 10, 2020 Category: Cytology Authors: Brest P, Benzaquen J, Klionsky DJ, Hofman P, Mograbi B Tags: Autophagy Source Type: research
MERIT, a cellular system coordinating lysosomal repair, removal and replacement.
Abstract Membrane integrity is essential for cellular survival and function. The spectrum of mechanisms protecting cellular and intracellular membranes is not fully known. Our recent work has uncovered a cellular system termed MERIT for lysosomal membrane repair, removal and replacement. Specifically, lysosomal membrane damage induces, in succession, ESCRT-dependent membrane repair, macroautophagy/autophagy-dominant removal of damaged lysosomes, and initiation of lysosomal biogenesis via transcriptional programs. The MERIT system is governed by galectins, a family of cytosolically synthesized lectins recognizing &...
Source: Autophagy - June 10, 2020 Category: Cytology Authors: Jia J, Claude-Taupin A, Gu Y, Choi SW, Peters R, Bissa B, Mudd MH, Allers L, Pallikkuth S, Lidke KA, Salemi M, Phinney B, Mari M, Reggiori F, Deretic V Tags: Autophagy Source Type: research
Atg21 organizes Atg8 lipidation at the contact of the vacuole with the phagophore.
Abstract Coupling of Atg8 to phosphatidylethanolamine is crucial for the expansion of the crescent-shaped phagophore during cargo engulfment. Atg21, a PtdIns3P-binding beta-propeller protein, scaffolds Atg8 and its E3-like complex Atg12-Atg5-Atg16 during lipidation. The crystal structure of Atg21, in complex with the Atg16 coiled-coil domain, showed its binding at the bottom side of the Atg21 beta-propeller. Our structure allowed detailed analyses of the complex formation of Atg21 with Atg16 and uncovered the orientation of the Atg16 coiled-coil domain with respect to the membrane. We further found that Atg21 was ...
Source: Autophagy - June 9, 2020 Category: Cytology Authors: Munzel L, Neumann P, Otto FB, Krick R, Metje-Sprink J, Kroppen B, Karedla N, Enderlein J, Meinecke M, Ficner R, Thumm M Tags: Autophagy Source Type: research
Live imaging of intra-lysosome pH in cell lines and primary neuronal culture using a novel genetically encoded biosensor.
i M Abstract Disorders of lysosomal physiology have increasingly been found to underlie the pathology of a rapidly growing cast of neurodevelopmental disorders and sporadic diseases of aging. One cardinal aspect of lysosomal (dys)function is lysosomal acidification in which defects trigger lysosomal stress signaling and defects in proteolytic capacity. We have developed a genetically encoded ratiometric probe to measure lysosomal pH coupled with a purification tag to efficiently purify lysosomes for both proteomic and in vitro evaluation of their function. Using our probe, we showed that lysosomal pH is remarkably...
Source: Autophagy - June 9, 2020 Category: Cytology Authors: Ponsford AH, Ryan TA, Raimondi A, Cocucci E, Wycislo SA, Fröhlich F, Swan LE, Stagi M Tags: Autophagy Source Type: research
Streptococcus pneumoniae promotes its own survival via choline-binding protein CbpC-mediated degradation of ATG14.
In this study, we explore the biological functions of Cbps and reveal their roles in manipulating the autophagic process. Specifically, we found that CbpC-activated autophagy takes place via its interactions with ATG14 (autophagy related 14) and SQSTM1/p62 (sequestosome1). Importantly, CbpC dampens host autophagy by promoting ATG14 degradation via the ATG14-CbpC-SQSTM1/p62 axis. CbpC-induced reductions in ATG14 levels result in impaired ATG14-STX17 complex formation. In pneumococcal-infected cells, ATG14 levels are dramatically reduced in a CbpC-dependent manner that results in suppression of autophagy-mediated degradation...
Source: Autophagy - June 8, 2020 Category: Cytology Authors: Shizukuishi S, Ogawa M, Ryo A, Ohnishi M Tags: Autophagy Source Type: research
Vac8 determines phagophore assembly site vacuolar localization during nitrogen starvation-induced autophagy.
Abstract Macroautophagy/autophagy is a key catabolic process in which different cellular components are sequestered inside double-membrane vesicles called autophagosomes for subsequent degradation. In yeast, autophagosome formation occurs at the phagophore assembly site (PAS), a specific perivacuolar location that works as an organizing center for the recruitment of different autophagy-related (Atg) proteins. How the PAS is localized to the vacuolar periphery is not well understood. Here we show that the vacuolar membrane protein Vac8 is required for correct vacuolar localization of the PAS. We provide evidence th...
Source: Autophagy - June 8, 2020 Category: Cytology Authors: Gatica D, Wen X, Cheong H, Klionsky DJ Tags: Autophagy Source Type: research