PaperPlayer biorxiv cell biology

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.14.251082v1?rss=1

Authors: Hwang, S., Cavaliere, P., Li, R., Zhu, L. J., Dephoure, N., Torres, E. M.

Abstract:

An extra copy of chromosome 21 causes Down syndrome, the most common genetic disease in humans. The mechanisms by which the aneuploid status of the cell, independent of the identity of the triplicated genes, contributes to the pathologies associated with this syndrome are not well defined. To characterize aneuploidy driven phenotypes in trisomy 21 cells, we performed global transcriptome, proteome, and phenotypic analysis of primary human fibroblasts from individuals with Patau (trisomy 13), Edwards (trisomy 18), or Down syndromes. On average, mRNA and protein levels show a 1.5 fold increase in all trisomies with a subset of proteins enriched for subunits of macromolecular complexes showing signs of post-transcriptional regulation. Furthermore, we show several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and an increased dependency on the serine-driven lipid biosynthesis pathway to proliferate. Our studies present a novel paradigm to study how aneuploidy contributes to Down syndrome.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.249664v1?rss=1

Authors: Rozario, A., Duwe, S., Elliott, C., Hargreaves, R. B., Dedecker, P., Whelan, D. R., Bell, T.

Abstract:

Microtubule-interacting drugs, sometimes referred to as antimitotics, are used in cancer therapy to target and disrupt microtubules. However, their side effects require the development of safer drug regimens that still retain clinical efficacy. Currently, many questions remain regarding microtubule-interacting drugs at clinically relevant and ultra-low doses. Here, we use super-resolution microscopies (single molecule localization and optical fluctuation based) to reveal the initial microtubule dysfunctions caused by nanomolar concentrations of colcemid. Short exposure to 30 - 80 nM colcemid results in aberrant microtubule curvature while microtubule fragmentation is detected upon treatment with [≥]100 nM colcemid. Remarkably, even ultra-low doses (5 hours at <20 nM) led to subtle but significant microtubule architecture remodeling and suppression of microtubule dynamics. These challenges to microtubule function represent less severe precursor perturbations compared to the established antimitotic effects of microtubule-interacting drugs, and therefore offer potential for improved understanding and design of anti-cancer agents.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.249169v1?rss=1

Authors: Iamshanova, O., Gordienko, D., Folcher, A., Bokhobza, A., Shapovalov, G., Mariot, P., Allart, L., Desruelles, E., Spriet, C., Diez, R., Oullier, T., Marionneau-Lambot, S., Brisson, L., Geraci, S., Impheng, H., Lehenkyi, V., Haustrate, A., Mihalache, A., Gosset, P., Chadet, S., Lerondel, S., Retif, S., Le Mee, M., Sobilo, J., Roger, S., Fromont, G., Djamgoz, M., Clezardin, P., Monteil, A., Prevarskaya, N.

Abstract:

Cytosolic Ca2+ oscillations provide signaling input to several effector systems of the cell. These include neuronal development, migration and networking. Although similar signaling events are hijacked by highly aggressive cancer cells, the mechanism(s) driving the 'neuron-like' remodeling of the intracellular ionic signature upon cancer progression remains largely elusive. Here, we identify the 'neuronal' Na+ leak channel, NALCN, in metastatic cells at the hot spots of invadopodia formation and Ca2+ event initiation. Mechanistically, NALCN-mediated Na+ influx associates functionally with plasmalemmal and mitochondrial Na+/Ca2+ exchangers (NCX and NCLX), reactive oxygen species (ROS) and store-operated Ca2+ entry (SOCE)/endoplasmic reticulum Ca2+ uptake (SERCA) systems to generate intracellular Ca2+ oscillations. In turn, the oscillatory activity promotes Src-regulated actin remodeling, Ca2+-dependent secretion of proteolytic enzymes and leads to invadopodogenesis, resulting in tumor progression and metastatic lesions in vivo . Thus, we have uncovered malignant assignment of NALCN giving rise to a critical intracellular Na+/Ca2+ signaling axis.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.244640v1?rss=1

Authors: LeBlond, N. D., Nunes, J. R. C., Smith, T. K. T., Robichaud, S., Gadde, S., Cote, M., Kemp, B. E., Ouimet, M., Fullerton, M. D.

Abstract:

The dysregulation of macrophage lipid metabolism drives atherosclerosis. AMP-activated protein kinase (AMPK) is a master regulator of cellular energetics and plays essential roles regulating macrophage lipid dynamics. Here, we investigated the consequences of atherogenic lipoprotein-induced foam cell formation on downstream immunometabolic signaling in primary mouse macrophages. A variety of atherogenic low-density lipoproteins (acetylated, oxidized and aggregated forms) activated AMPK signaling in a manner that was in part, due to CD36 and calcium-related signaling. In quiescent macrophages, basal AMPK signaling was crucial for maintaining markers of lysosomal homeostasis, as well as levels of key components in the lysosomal expression and regulation network. Moreover, AMPK activation resulted in targeted up-regulation of members of this network via transcription factor EB. However, in lipid-induced macrophage foam cells, neither basal AMPK signaling nor its activation affected lysosomal-associated programs. These results suggest that while the sum of AMPK signaling in cultured macrophages may be anti-atherogenic, atherosclerotic input dampens the regulatory capacity of AMPK signaling.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.249276v1?rss=1

Authors: Yperman, K., Wang, J., Eeckhout, D., Winkler, J., Vu, L., Vandorpe, M., Grones, P., Mylle, E., Kraus, M., Merceron, R., Nolf, J., Mor, E., De Bruyn, P., Loris, R., Potocky, M., Savvides, S. N., De Rybel, B., De Jaeger, G., Van Damme, D., Pleskot, R.

Abstract:

All eukaryotic cells rely on endocytosis to regulate the plasma membrane proteome and lipidome. Most eukaryotic groups, with the exception of fungi and animals, have retained the evolutionary ancient TSET complex as a regulator of endocytosis. Despite the presence of similar building blocks in TSET, compared to other coatomer complexes, structural insight into this adaptor complex is lacking. Here, we elucidate the molecular architecture of the octameric plant TSET complex (TPLATE complex/TPC) using an integrative structural approach. This allowed us to describe a plant-specific connection between the TML subunit and the AtEH/Pan1 proteins and show a direct interaction between the complex and the plasma membrane without the need for any additional protein factors. Furthermore, we identify the appendage of TPLATE as crucial for complex assembly. Structural elucidation of this ancient adaptor complex vastly advances our functional as well as evolutionary insight into the process of endocytosis.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.12.246090v1?rss=1

Authors: Brito, C., Mesquita, F. S., Osorio, D., Pereira, J., Billington, N., Sellers, J. R., Cabanes, D., Xavier de Carvalho, A., Sousa, S.

Abstract:

Non-muscle myosin 2A (NM2A) is a key cytoskeletal enzyme that along with actin assembles into actomyosin filaments inside cells. NM2A is fundamental in cellular processes requiring force generation such as cell adhesion, motility and cell division, and plays important functions in different stages of development and during the progression of viral and bacterial infections. We previously identified at the motor domain of the NM2A, a novel Src-dependent tyrosine phosphorylation on residue 158 (pTyr158), which is promoted by Listeria monocytogenes infection. Despite the central role of NM2A in several cell biology processes, the pTyr at this specific residue had never been reported. Here we showed that LLO, a toxin secreted by Listeria, is sufficient to trigger NM2A pTyr158 by activating Src, which coordinates actomyosin remodeling. We further addressed the role of NM2A pTyr158 on the organization and dynamics of the actomyosin cytoskeleton and found that by controlling the activation of the NM2A, the status of the pTyr158 alters cytoskeletal organization, dynamics of focal adhesions and cell motility, without affecting NM2A enzymatic activity in vitro. Ultimately, by using Caenorhabditis elegans as a model to assess the role of this pTyr158 in vivo, we found that the status of the pTyr158 has implications in gonad function and is required for organism survival under stress conditions. We conclude that the fine control of the NM2A pTyr158 is required for cell cytoskeletal remodeling and dynamics, and we propose Src-dependent NM2A pTyr158 as a novel layer of regulation of the actomyosin cytoskeleton.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.12.248658v1?rss=1

Authors: Medley, J. C., DiPanni, J. R., Schira, L., Shaffou, B., Sebou, B., SONG, M. H.

Abstract:

Aberrant centrosome numbers are associated with human cancers. The levels of centrosome regulators positively correlate with centrosome number. Thus, tight control of centrosome protein levels is critical. In Caenorhabditis elegans, the anaphase-promoting complex/cyclosome and co-activator FZR-1 (APC/CFZR-1) ubiquitin ligase negatively regulates centrosome assembly through SAS-5 degradation. In this study, we identify the C. elegans ZYG-1 (Plk4 in human) as a new substrate of APC/CFZR-1. Inhibiting APC/CFZR-1 or mutating a ZYG-1 destruction (D)-box leads to elevated ZYG-1 levels at centrosomes, restoring bipolar spindles and embryonic viability to zyg-1 mutants, suggesting that APC/CFZR-1 targets ZYG-1 for proteasomal degradation via D-box motif. We also show the Slimb/{beta}TrCP-binding (SB) motif is critical for ZYG-1 degradation, substantiating a conserved mechanism by which ZYG-1/Plk4 stability is regulated by SCF-Slimb/{beta}TrCP-dependent proteolysis via the conserved SB motif in C. elegans. Furthermore, inhibiting both APC/CFZR-1and SCF-Slimb/{beta}TrCP, by co-mutating ZYG-1 SB and D-box motifs, stabilizes ZYG-1 in an additive manner, conveying that APC/CFZR-1 and SCF-Slimb/{beta}TrCP ubiquitin ligases function cooperatively for timely ZYG-1 destruction in C. elegans embryos where ZYG-1 activity remains at threshold level to ensure normal centrosome number.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.12.246843v1?rss=1

Authors: Serrano, A., Schwarz, N., Hammadeh, H. H., Brandt, U., Fleissner, A.

Abstract:

Somatic cell fusion is widely studied in the filamentous fungus Neurospora crassa. The interaction of genetically identical germlings is mediated by a signaling mechanism in which the cells take turns in signal-sending and receiving. The switch between these physiological states is represented by the alternating membrane recruitment of the SO protein and the MAPK MAK-2. This dialog-like behavior is observed until the cells establish physical contact, when the cell-wall-integrity MAK-1 is recruited to the contact area to control the final steps of the cell fusion process. This work revealed, for the first-time, an additional MAK-1-function during the tropic growth phase. Specific inhibition of MAK-1 during tropic-growth resulted in disassembly of the actin-aster, and mislocalization of SO and MAK-2. Similar defects were observed after the inhibition of the Rho-GTPase RAC-1, suggesting a functional link between them, being MAK-1 upstream of RAC-1. In contrast, after inhibition of MAK-2, the actin-aster stayed intact, however, its subcellular localization became instable within the cell-membrane. Together these observations led to a new working model, in which MAK-1 promotes the formation and stability of the actin-aster, while MAK-2 controls its positionning and cell growth directionality.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.249771v1?rss=1

Authors: Stracy, M., schweizer, J., Sherratt, D., kapanidis, A., Uphoff, S., Lesterlin, C.

Abstract:

Despite their diverse biochemical characteristics and functions, all DNA-binding proteins share the ability to accurately locate their target sites among the vast excess of non-target DNA. Towards identifying universal mechanisms of the target search, we used single-molecule tracking of 11 diverse DNA-binding proteins in living Escherichia coli. The mobility of these proteins during the target search was dictated by DNA interactions, rather than by their molecular weights. By generating cells devoid of all chromosomal DNA, we discovered that the nucleoid does not pose a physical barrier for protein diffusion, but significantly slows the motion of DNA-binding proteins through frequent short-lived DNA interactions. The representative DNA-binding proteins (irrespective of their size, concentration, or function) spend the majority (58-99%) of their search time bound to DNA and occupy as much as ~30% of the chromosomal DNA at any time. Chromosome-crowding likely has important implications for the function of all DNA-binding proteins.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.249458v1?rss=1

Authors: Zhang, C., Zhang, X., Guan, Y., Huang, X., Zhang, L., Tian, X.-L., Tao, W.

Abstract:

Chromatin architecture and gene expression profile undergo tremendous reestablishment during senescence. However, the regulatory mechanism between chromatin reconstruction and gene expression in senescence remain elusive. The chromatin accessibility is an excellent perspective to reveal the latent regulatory elements. Thus, we depicted the landscapes of chromatin accessibility and gene expression during HUVECs senescence. We found that chromatin accessibilities are re-distributed during senescence. The senescence related increased accessible regions (IARs) and the decreased accessible regions (DARs) are mainly distributed in distal intergenic regions. The DARs are correlated with the function declines caused by senescence, whereas the IARs are involved in the regulation for senescence program. Moreover, the heterochromatin contributes most of IARs in senescent cells. We identified that the AP-1 transcription factors, especially ATF3 is responsible for driving chromatin accessibility reconstruction in IARs. In particular, DNA methylation is negatively correlated with chromatin accessibility during senescence. AP-1 motifs with low DNA methylation may improve their binding affinity in IARs and further opens the chromatin nearby. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program. And we identified a cellular senescence regulator, AP-1, which promotes senescence through organizing the accessibility profile in IARs.

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