Tissue tension and not interphase cell shape determines cell division orientation in the Drosophila follicular epithelium
We examined the orientation of cell divisions with respect to the planar tissue axis and found a bias toward the primary direction of tissue expansion. However, interphase cell shapes demonstrate the opposite bias. Hertwig's rule, which holds that cell elongation determines division orientation, is therefore broken in this tissue. This observation cannot be explained by the anisotropic activity of the conserved Pins/Mud spindle-orienting machinery, which controls division orientation in the apical–basal axis and planar division orientation in other epithelial tissues. Rather, cortical tension at the apical surface tr...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Finegan, T. M., Na, D., Cammarota, C., Skeeters, A. V., Nadasi, T. J., Dawney, N. S., Fletcher, A. G., Oakes, P. W., Bergstralh, D. T. Tags: Cell Adhesion, Polarity & Cytoskeleton, Development & Differentiation Articles Source Type: research
Clustering of Tau fibrils impairs the synaptic composition of {alpha}3-Na+/K+-ATPase and AMPA receptors
We report that fibrillar Tau forms clusters at the plasma membrane following lateral diffusion. We found that the fibrils interact with the Na+/K+-ATPase (NKA) and AMPA receptors. The consequence of the clustering is a reduction in the amount of α3-NKA and an increase in the amount of GluA2-AMPA receptor at synapses. Furthermore, fibrillar Tau destabilizes functional NKA complexes. Tau and α-synuclein aggregates often co-exist in patients’ brains. We now show evidences for cross-talk between these pathogenic aggregates with α-synuclein fibrils dramatically enhancing fibrillar Tau clustering and syna...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Shrivastava, A. N., Redeker, V., Pieri, L., Bousset, L., Renner, M., Madiona, K., Mailhes-Hamon, C., Coens, A., Buee, L., Hantraye, P., Triller, A., Melki, R. Tags: Neuroscience Articles Source Type: research
R-loop formation during S phase is restricted by PrimPol-mediated repriming
During DNA replication, conflicts with ongoing transcription are frequent and require careful management to avoid genetic instability. R-loops, three-stranded nucleic acid structures comprising a DNA:RNA hybrid and displaced single-stranded DNA, are important drivers of damage arising from such conflicts. How R-loops stall replication and the mechanisms that restrain their formation during S phase are incompletely understood. Here, we show in vivo how R-loop formation drives a short purine-rich repeat, (GAA)10, to become a replication impediment that engages the repriming activity of the primase-polymerase PrimPol. Fu...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Svikovic, S., Crisp, A., Tan-Wong, S. M., Guilliam, T. A., Doherty, A. J., Proudfoot, N. J., Guilbaud, G., Sale, J. E. Tags: DNA Replication, Repair & Recombination Articles Source Type: research
Avidity-driven polarity establishment via multivalent lipid-GTPase module interactions
While Rho GTPases are indispensible regulators of cellular polarity, the mechanisms underlying their anisotropic activation at membranes have been elusive. Using the budding yeast Cdc42 GTPase module, which includes a guanine nucleotide exchange factor (GEF) Cdc24 and the scaffold Bem1, we find that avidity generated via multivalent anionic lipid interactions is a critical mechanistic constituent of polarity establishment. We identify basic cluster (BC) motifs in Bem1 that drive the interaction of the scaffold–GEF complex with anionic lipids at the cell pole. This interaction appears to influence lipid acyl chain ord...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Meca, J., Massoni-Laporte, A., Martinez, D., Sartorel, E., Loquet, A., Habenstein, B., McCusker, D. Tags: Cell Adhesion, Polarity & Cytoskeleton, Membrane & Intracellular Transport Articles Source Type: research
RagC phosphorylation autoregulates mTOR complex 1
The mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) controls cell growth, proliferation, and metabolism in response to diverse stimuli. Two major parallel pathways are implicated in mTORC1 regulation including a growth factor-responsive pathway mediated via TSC2/Rheb and an amino acid-responsive pathway mediated via the Rag GTPases. Here, we identify and characterize three highly conserved growth factor-responsive phosphorylation sites on RagC, a component of the Rag heterodimer, implicating cross talk between amino acid and growth factor-mediated regulation of mTORC1. We find that RagC phosphorylation is...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Yang, G., Humphrey, S. J., Murashige, D. S., Francis, D., Wang, Q.-P., Cooke, K. C., Neely, G. G., James, D. E. Tags: Development & Differentiation, Signal Transduction Articles Source Type: research
Structure and transformation of bacteriophage A511 baseplate and tail upon infection of Listeria cells
Contractile injection systems (bacteriophage tails, type VI secretions system, R-type pyocins, etc.) utilize a rigid tube/contractile sheath assembly for breaching the envelope of bacterial and eukaryotic cells. Among contractile injection systems, bacteriophages that infect Gram-positive bacteria represent the least understood members. Here, we describe the structure of Listeria bacteriophage A511 tail in its pre- and post-host attachment states (extended and contracted, respectively) using cryo-electron microscopy, cryo-electron tomography, and X-ray crystallography. We show that the structure of the tube-baseplate compl...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Guerrero-Ferreira, R. C., Hupfeld, M., Nazarov, S., Taylor, N. M., Shneider, M. M., Obbineni, J. M., Loessner, M. J., Ishikawa, T., Klumpp, J., Leiman, P. G. Tags: Microbiology, Virology & Host Pathogen Interaction, Structural Biology Articles Source Type: research
Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria
Accumulation of the protein tau characterises Alzheimer's disease and other tauopathies, including familial forms of frontotemporal dementia (FTD) that carry pathogenic tau mutations. Another hallmark feature of these diseases is the accumulation of dysfunctional mitochondria. Although disease-associated tau is known to impair several aspects of mitochondrial function, it is still unclear whether it also directly impinges on mitochondrial quality control, specifically Parkin-dependent mitophagy. Using the mito-QC mitophagy reporter, we found that both human wild-type (hTau) and FTD mutant tau (hP301L) inhibited mitophagy i...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Cummins, N., Tweedie, A., Zuryn, S., Bertran-Gonzalez, J., Götz, J. Tags: Autophagy & Cell Death, Membrane & Intracellular Transport, Neuroscience Articles Source Type: research
Developmental and functional heterogeneity of white adipocytes within a single fat depot
Recent studies suggest that, even within a single adipose depot, there may be distinct subpopulations of adipocytes. To investigate this cellular heterogeneity, we have developed multiple conditionally immortalized clonal preadipocyte lines from white adipose tissue of mice. Analysis of these clones reveals at least three white adipocyte subpopulations. These subpopulations have differences in metabolism and differentially respond to inflammatory cytokines, insulin, and growth hormones. These also have distinct gene expression profiles and can be tracked by differential expression of three marker genes: Wilms’ tumor ...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Lee, K. Y., Luong, Q., Sharma, R., Dreyfuss, J. M., Ussar, S., Kahn, C. R. Tags: Development & Differentiation, Metabolism Articles Source Type: research
hnRNP L-dependent protection of normal mRNAs from NMD subverts quality control in B cell lymphoma
The human nonsense-mediated mRNA decay pathway (NMD) performs quality control and regulatory functions within complex post-transcriptional regulatory networks. In addition to degradation-promoting factors, efficient and accurate detection of NMD substrates involves proteins that safeguard normal mRNAs. Here, we identify hnRNP L as a factor that protects mRNAs with NMD-inducing features including long 3'UTRs. Using biochemical and transcriptome-wide approaches, we provide evidence that the susceptibility of a given transcript to NMD can be modulated by its 3'UTR length and ability to recruit hnRNP L. Integrating these findi...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Kishor, A., Ge, Z., Hogg, J. R. Tags: Cancer, RNA Biology Articles Source Type: research
A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity
Both protein quality and mitochondrial quality are vital for the cellular activity, and impaired proteostasis and mitochondrial dysfunction are common etiologies of aging and age-related disorders. Here, we report that the mitochondrial outer membrane protein FUNDC1 interacts with the chaperone HSC70 to promote the mitochondrial translocation of unfolded cytosolic proteins for degradation by LONP1 or for formation of non-aggresomal mitochondrion-associated protein aggregates (MAPAs) upon proteasome inhibition in cultured human cells. Integrative approaches including csCLEM, Apex, and biochemical analysis reveal that MAPAs ...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Li, Y., Xue, Y., Xu, X., Wang, G., Liu, Y., Wu, H., Li, W., Wang, Y., Chen, Z., Zhang, W., Zhu, Y., Ji, W., Xu, T., Liu, L., Chen, Q. Tags: Autophagy & Cell Death, Post-translational Modifications, Proteolysis & Proteomics, Protein Biosynthesis & Quality Control Articles Source Type: research
A novel form of JARID2 is required for differentiation in lineage-committed cells
Polycomb repressive complex-2 (PRC2) is a group of proteins that play an important role during development and in cell differentiation. PRC2 is a histone-modifying complex that catalyses methylation of lysine 27 of histone H3 (H3K27me3) at differentiation genes leading to their transcriptional repression. JARID2 is a co-factor of PRC2 and is important for targeting PRC2 to chromatin. Here, we show that, unlike in embryonic stem cells, in lineage-committed human cells, including human epidermal keratinocytes, JARID2 predominantly exists as a novel low molecular weight form, which lacks the N-terminal PRC2-interacting domain...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Al-Raawi, D., Jones, R., Wijesinghe, S., Halsall, J., Petric, M., Roberts, S., Hotchin, N. A., Kanhere, A. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Stem Cells Articles Source Type: research
TFEB controls vascular development by regulating the proliferation of endothelial cells
Transcription factor TFEB is thought to control cellular functions—including in the vascular bed—primarily via regulation of lysosomal biogenesis and autophagic flux. Here, we report that TFEB also orchestrates a non-canonical program that controls the cell cycle/VEGFR2 pathway in the developing vasculature. In endothelial cells, TFEB depletion halts proliferation at the G1-S transition by inhibiting the CDK4/Rb pathway. TFEB-deficient cells attempt to compensate for this limitation by increasing VEGFR2 levels at the plasma membrane via microRNA-mediated mechanisms and controlled membrane trafficking. TFEB stim...
Source: EMBO Journal - February 1, 2019 Category: Molecular Biology Authors: Doronzo, G., Astanina, E., Cora, D., Chiabotto, G., Comunanza, V., Noghero, A., Neri, F., Puliafito, A., Primo, L., Spampanato, C., Settembre, C., Ballabio, A., Camussi, G., Oliviero, S., Bussolino, F. Tags: Cell Cycle, Transcription, Vascular Biology & Angiogenesis Articles Source Type: research
Rab29 activation of the Parkinson's disease-associated LRRK2 kinase
(Source: EMBO Journal)
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Purlyte, E., Dhekne, H. S., Sarhan, A. R., Gomez, R., Lis, P., Wightman, M., Martinez, T. N., Tonelli, F., Pfeffer, S. R., Alessi, D. R. Tags: Corrigendum Source Type: research
CFTR is not a gluten lover either
Coeliac disease (CD) is an inflammatory autoimmune disease caused by ingestion of gluten proteins, mainly gliadin. Undigested gliadin proline-rich peptides trigger the innate and adaptive immune response, resulting in intestinal cell stress and damage. A new study by Villella et al (2019) addressing the unclear primary cause of intestinal cell stress reports that gliadin peptides inhibit the function of the chloride and bicarbonate channel CFTR, causing intestinal cell stress, which is sufficient to trigger CD symptoms. Notably, CFTR potentiators used to treat cystic fibrosis effectively rescue CFTR function and marke...
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Vachel, L., Muallem, S. Tags: Immunology, Membrane & Intracellular Transport, Molecular Biology of Disease News [amp ] Views Source Type: research
Fat-fated microglial dysfunction
Patients with lysosomal storage disorders (LSDs) exhibit activated microglia in the brain, but the mechanisms underlying microglial activation and contribution to disease pathology are unclear. In this issue, Gabandé-Rodríguez et al present intriguing data to suggest a protective function for microglia that is corrupted by sphingolipid lysosomal overload in Niemann-Pick disease type A. (Source: EMBO Journal)
Source: EMBO Journal - January 15, 2019 Category: Molecular Biology Authors: Silvin, A., Ginhoux, F. Tags: Membrane & Intracellular Transport, Neuroscience News [amp ] Views Source Type: research
