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Audio versions of bioRxiv paper abstracts

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Audio versions of bioRxiv paper abstracts

    Consequences of aneuploidy in human fibroblasts with trisomy 21

    Consequences of aneuploidy in human fibroblasts with trisomy 21

    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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    Ultra-Low Colcemid Doses Induce Microtubule Dysfunction as Revealed by Super-Resolution Microscopy

    Ultra-Low Colcemid Doses Induce Microtubule Dysfunction as Revealed by Super-Resolution Microscopy

    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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    Malignant assignment of neuronal Na+ leak channel, NALCN: governor of Ca2+ oscillations-encoded invadopodogenesis

    Malignant assignment of neuronal Na+ leak channel, NALCN: governor of Ca2+ oscillations-encoded invadopodogenesis

    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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    Foam cell induction activates AMPK but uncouples its regulation of autophagy and lysosomal homeostasis

    Foam cell induction activates AMPK but uncouples its regulation of autophagy and lysosomal homeostasis

    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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    The TPLATE subunit is essential for structural assembly of the endocytic TSET complex

    The TPLATE subunit is essential for structural assembly of the endocytic TSET complex

    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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    Src-dependent NM2A tyrosine-phosphorylation regulates actomyosin dynamics

    Src-dependent NM2A tyrosine-phosphorylation regulates actomyosin dynamics

    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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