Refereed Preprints

Review Commons provides authors with a Refereed Preprint, which includes the authors’ manuscript, reports from a single round of peer review and the authors’ response. These Refereed Preprints are transferred on the author’s behalf to bioRxiv. The most recently-completed Review Commons peer-reviews are listed below, with the most recently posted reviews at the top.

Latest Refereed Preprints

Cell Biology | 13 Apr 2020
Mitochondrial dysfunction causes muscle wasting (or atrophy) in many diseases and probably also during aging. The underlying mechanism is unclear. Accumulating evidence suggests that substantial levels of bioenergetic deficiency and oxidative stress are insufficient by themselves to intrinsically cause muscle wasting, raising the possibility that non-bioenergetic factors may contribute to mitochondria-induced muscle wasting. In this report, we show that chronic adaptation to mitochondria-induced…
Cell Biology | 14 Apr 2020

Alpha-satellite RNA transcripts are repressed by centromere-nucleolus associations

Leah Bury, Brittania Moodie, Liliana S. McKay, Karen H. Miga, Iain M. Cheeseman

Centromeres play a fundamental role in chromosome segregation. Although originally thought to be silent chromosomal regions, centromeres are actively transcribed. However, the behavior and contributions of centromere-derived RNAs have remained unclear. Here, we used single-molecule fluorescence in-situ hybridization (smFISH) to detect alpha-satellite RNA transcripts in intact human cells. We find that alpha-satellite RNA smFISH foci fluctuate in their levels over the cell cycle and do not remain…
Cell Biology | 18 Mar 2020

Optogenetic control of PRC1 reveals its role in chromosome alignment at the metaphase plate

Mihaela Jagrić, Patrik Risteski, Jelena Martinčić, Ana Milas, Iva M. Tolić

During metaphase, chromosome position at the spindle equator is mainly regulated by the forces exerted by kinetochore microtubules. However, the role of forces arising from mechanical coupling between sister kinetochore fibers and bridging fibers, whose antiparallel microtubules are crosslinked by protein regulator of cytokinesis 1 (PRC1), in chromosome alignment is unknown. Here we develop an optogenetic approach for acute removal of PRC1 and show that PRC1 promotes kinetochore alignment. PRC1 …
Developmental Biology | 21 Feb 2020

An asymmetry in the frequency and position of mitosis in the epiblast precedes gastrulation and suggests a role for mitotic rounding in cell delamination during primitive streak epithelial-mesenchymal transition

Evangéline Despin-Guitard, Navrita Mathiah, Matthew Stower, Wallis Nahaboo, Elif Sema Eski, Sumeet Pal Singh, Shankar Srinivas, Isabelle Migeotte

The epiblast, a pseudostratified epithelium, is the precursor for the three main germ layers required for body shape and organogenesis: ectoderm, mesoderm, and endoderm. At gastrulation, a subpopulation of epiblast cells constitutes a transient posteriorly located structure called the primitive streak, where cells that undergo epithelial-mesenchymal transition make up the mesoderm and endoderm lineages.In order to observe the behavior of individual cells, epiblast cells were labeled ubiquitously…
Neuroscience | 05 Feb 2020

Protective anti-prion antibodies in human immunoglobulin repertoires

Assunta Senatore, Karl Frontzek, Marc Emmenegger, Andra Chincisan, Marco Losa, Regina Reimann, Geraldine Horny, Jingjing Guo, Sylvie Fels, Silvia Sorce, Caihong Zhu, Nathalie George, Stefan Ewert, Thomas Pietzonka, Simone Hornemann, Adriano Aguzzi

Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here we identified >6000 PrP-binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage-derived antibo…
Cancer Biology | 11 Jan 2020
Genetic interactions, such as synthetic lethal effects, can now be systematically identified in cancer cell lines using high-throughput genetic perturbation screens. Despite this advance, few genetic interactions have been reproduced across multiple studies and many appear highly context-specific. Understanding which genetic interactions are robust in the face of the molecular heterogeneity observed in tumours and what factors influence this robustness could streamline the identification of ther…
Physiology | 27 Feb 2020

Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenic response in subcutaneous adipose tissue

Katia Aquilano, Francesca Sciarretta, Riccardo Turchi, Bo-Han Li, Marco Rosina, Veronica Ceci, Giulio Guidobaldi, Simona Arena, Chiara D’Ambrosio, Matteo Audano, Illari Salvatori, Barbara Colella, Raffaella Faraonio, Concita Panebianco, Valerio Pazienza, Donatella Caruso, Nico Mitro, Sabrina Di Bartolomeo, Andrea Scaloni, Jing-Ya Li, Daniele Lettieri-Barbato

Low-protein/high-carbohydrate (LPHC) diet promotes metabolic health and longevity in adult humans and animal models. However, the complex molecular underpinnings of how LPHC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LPHC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous white adipose tissue (sWAT). In particular, we measure…
Cell Biology | 23 Feb 2020

Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton

Wenqing Zhou, Alan Y. Hsu, Yueyang Wang, Tianqi Wang, Jacob Jeffries, Xu Wang, Haroon Mohammad, Mohamed N. Seleem, David Umulis, Qing Deng

Neutrophils rely on glycolysis for energy production. How mitochondria regulate neutrophil function is not fully understood. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (Mfn2) regulates neutrophil homeostasis in vivo. Mfn2-deficient neutrophils are released from the hematopoietic tissue and trapped in the vasculature in zebrafish embryos. Human neutrophil-like cells deficient with MFN2 fail to arrest on activated endothelium under sheer stress or perform chemot…
Genomics | 05 May 2020

Retrocopying expands the functional repertoire of APOBEC3 antiviral proteins in primates

Lei Yang, Michael Emerman, Harmit S. Malik, Richard N. McLaughlin

Host-virus arms races are inherently asymmetric; viruses evolve much more rapidly than host genomes. Thus, there is high interest in discovering mechanisms by which host genomes keep pace with rapidly evolving viruses. One family of restriction factors, the APOBEC3 (A3) cytidine deaminases, has undergone positive selection and expansion via segmental gene duplication and recombination. Here, we show that new copies of A3 genes have also been created in primates by reverse trans…
Neuroscience | 11 Feb 2020

The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration

Amanda K. Engstrom, Alicia C. Walker, Rohitha A. Moudgal, Dexter A. Myrick, Stephanie M. Kyle, David J. Katz

Tauopathies are a class of neurodegenerative diseases associated with pathological tau. However, the mechanism through which tau contributes to neurodegeneration remains unknown. Previously, our lab implicated the histone demethylase LSD1 in tau-induced neurodegeneration by showing that LSD1 localizes to pathological tau aggregates in Alzheimer’s disease cases, and that it is continuously required for the survival of hippocampal and cortical neurons in mice. Here, we utilize the P301S tauopath…
Neuroscience | 11 Jan 2020

Genome-wide transcriptomics identifies an early preclinical signature of prion infection

Silvia Sorce, Mario Nuvolone, Giancarlo Russo, Andra Chincisan, Daniel Heinzer, Merve Avar, Manuela Pfammatter, Petra Schwarz, Mirzet Delic, Simone Hornemann, Despina Sanoudou, Claudia Scheckel, Adriano Aguzzi

The clinical course of prion diseases is accurately predictable despite long latency periods, suggesting that prion pathogenesis is driven by precisely timed molecular events. We constructed a searchable genome-wide atlas of mRNA abundance, splicing and editing alterations during the course of disease in prion-inoculated mice. Prion infection induced transient changes in mRNA abundance and processing already at eight weeks post inoculation, well ahead of any neuropathological and clinical signs.…
Cell Biology | 13 May 2019

The Glycolytic Protein Phosphofructokinase Dynamically Relocalizes into Subcellular Compartments with Liquid-like Properties in vivo

SoRi Jang, Zhao Xuan, Ross C. Lagoy, Louise M. Jawerth, Ian Gonzalez, Milind Singh, Shavanie Prashad, Hee Soo Kim, Avinash Patel, Dirk R. Albrecht, Anthony A. Hyman, Daniel A. Colón-Ramos

While much is known about the biochemical regulation of glycolytic enzymes, less is understood about how they are organized inside cells. Here we built a hybrid microfluidic-hydrogel device for use in Caenorhabditis elegans to systematically examine and quantify the dynamic subcellular localization of the rate-limiting enzyme of glycolysis, phosphofructokinase-1/PFK-1.1. We determine that endogenous PFK-1.1 localizes to distinct, tissue-specific subcellular compartments in vivo
Cell Biology | 12 Feb 2020

Transcytosis via the late endocytic pathway as a cell morphogenetic mechanism

R Mathew, LD Rios-Barrera, P Machado, Y Schwab, M Leptin

Plasma membranes fulfil many physiological functions. In polarized cells, different membrane compartments take on specialized roles, each being allocated correct amounts of membrane. The Drosophila tracheal system, an established tubulogenesis model, contains branched terminal cells with subcellular tubes formed by apical plasma membrane invagination. We show that apical endocytosis and late endosome-mediated trafficking determine the membrane allocation to the apical and basal membrane domains.…
Molecular Biology | 13 Dec 2019

Unveiling the dimer/monomer propensities of Smad MH1-DNA complexes

Lidia Ruiz, Zuzanna Kaczmarska, Tiago Gomes, Eric Aragón, Carles Torner, Regina Freier, Błażej Bagiński, Pau Martin-Malpartida, Natàlia de Martin Garrido, José A. Márquez, Tiago N. Cordeiro, Radoslaw Pluta, Maria J. Macias

R-Smads are effectors of the transforming growth factor β (TGFβ) superfamily and along with Smad4 form trimers to interact with other transcription factors and with DNA. The 5GC-DNA complexes determined here by X-ray crystallography for Smad5 and Smad8 proteins corroborate that all MH1 domains bind SBE and 5GC sites similarly, although Smad2/3/4 MH1 domains bind DNA as monomers whereas Smad1/5/8 form helix-swapped dimers. To examine the relevance of the dimerization phenomenon and to exclude a…
Cell Biology | 21 Jan 2020

KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity

Marjorie Fournier, Jean-Yves Bleuyard, Anthony M. Couturier, Jessica Ellins, Svenja Hester, Stephen J. Smerdon, László Tora, Fumiko Esashi

The tumour suppressor PALB2 stimulates error-free repair of DNA breaks, whilst its steady-state chromatin association protects active genes from genotoxic stress. Here, we report that the lysine acetyltransferases 2A and 2B (KAT2A/B), commonly known to promote transcriptional activation, acetylate the PALB2 chromatin association motif (ChAM), providing a dynamic regulatory mechanism for PALB2. ChAM acetylation within a cluster of seven lysine residues (7K), detected in the chromatin-enriched fra…
Microbiology | 13 Feb 2020

Second messenger control of mRNA translation by dynamic ribosome modification

Lucia Grenga, Richard Howard Little, Govind Chandra, Stuart Daniel Woodcock, Gerhard Saalbach, Richard James Morris, Jacob George Malone

Control of mRNA translation is a crucial regulatory mechanism used by bacteria to respond to their environment. In the soil bacterium Pseudomonas fluorescens, RimK modifies the C-terminus of ribosomal protein RpsF to influence important aspects of rhizosphere colonisation through proteome remodelling. In this study, we show that RimK activity is itself under complex, multifactorial control by the co-transcribed phosphodiesterase trigger enzyme (RimA) and a polyglutamate-specific proteas…