Cell Biology

eLife assessment

The authors studied the mechanisms by which dead cells are removed from the wounded skin in a process called efferocytosis. By analyzing different cell populations in the skin, the authors find that proteins involved in mediating the cell death and marking the cells as undergoing this process are elevated during distinct times in the wound healing program. Interestingly, these same proteins are elevated even higher in diabetic wounds. Finally the authors demonstrate that blocking the process of efferocytosis alters the wound healing program, thus illustrating its importance in effective wound repair.

eLife assessment

The manuscript by Jingsong Zhou and colleagues uncovers why the extraocular muscles (EOMs) are preserved while other muscles undergo degenerative changes in amyotrophic lateral sclerosis (ALS). In this work, the authors have used a mouse model of familial ALS that carries a G93A mutation in the Sod1 gene to demonstrate that NaBu treatment partially restores the integrity of NMJ in the limb and diaphragm muscles of G93A mice. The findings of the study offer important information that EOMs are spared in ALS because they produce protective factors for the NMJ and, more specifically, factors secreted by EOM-derived satellite cells. While most of the experimental approaches are convincing, the use of sodium butyrate (NaBu) in this study needs further investigation, as NaBu might have a variety of biological effects. Overall, this work may help develop future therapeutic interventions for patients with ALS.

eLife assessment

In this study, the authors develop a strategy for fluorophore-tagging endogenous proteins in human induced pluripotent stem cells (iPSCs) using a split mNeonGreen approach, and they conclude that the system will be appropriate for performing live imaging studies of highly dynamic cellular processes such as cytokinesis in iPSCs. Experimentally, the methods are solid, and the data presented support the authors' conclusions. Overall, these methodologies should be useful to a wide audience of cell biologists who want to study protein localization and dynamics at endogenous levels in iPSCs.

eLife assessment

This is an important study for understanding the pathogenesis of ulcerative colitis. It convincingly demonstrates reduced levels of the vesicular trafficking protein Rab7 in ulcerative colitis and Crohn's disease, leading to altered levels of calcium-activated chloride channel regulator 1 (CLCA1) and subsequent mucin dysregulation, highlighting Rab7's significance in gut homeostasis maintenance. The manuscript advances the field as it provides insights into a novel regulatory pathway implicated in ulcerative colitis, potentially paving the way for the development of targeted therapeutic interventions.

eLife assessment

This study presents initial findings in the generation of 3D cell constructs from endometrial cell mixtures seeded in Matrigel scaffold and treated with hormones as a proof of concept. While the study findings are valuable, functional validation to demonstrate its robustness is lacking, and therefore the strength of evidence is incomplete. The term organoids might not be appropriate to describe this in vitro model.

eLife assessment

The study presents important findings regarding a transcription-independent component of the early recovery of proteasome activity from a short pulse of proteasome inhibitor treatment, which has not been appreciated before and which is independent of the DDI2-NRF2 axis. While the evidence is in principle solid, with recapitulation in several cell line models, the proposed alternative underlying mechanism, namely regulation at the level of proteasome assembly, lacks experimental support, and at this point remain speculative.

eLife assessment

This fundamental study addresses a long-standing mystery in splicing regulation: does splicing occur co- or post-transcriptionally? The authors provide compelling evidence demonstrating that splicing can occur post-transcriptionally at a transcription site proximal zone, changing the way we think about splicing.

eLife assessment

This valuable study sheds light on the pivotal role of alterations in chondrocyte glycan metabolism in two contexts: The onset of cartilage degeneration and early onset of osteoarthritis (OA). The action is through hypertrophic differentiation of chondrocytes, a finding that provides insights into the identification of nascent markers for early-stage OA. The evidence supporting the claims is solid, with the authors clearly demonstrating the role of articular cartilage corefucosylation in the development of OA. The authors' inferences would be further enhanced through future experiments aimed at analyzing the mechanisms underlying the changes in glycometabolism in cartilage.

eLife assessment

This useful work provides insight into the formation of associations between the nucleolus and Promyelocytic leukemia nuclear bodies (PML-NBs). The work showed that these associations depend on both the formation of DNA double-strand breaks and the impaired RNA Polymerase I transcription, and also is modulated by the homologous recombination. The evidence supporting the claims is incomplete and the paper needs more experimental support on the dynamics of the association and mechanistic insight into the signaling for its formation.

eLife assessment

This study provides the fundamental insight that TGN46, a single-pass membrane protein, acts as a cargo receptor for proteins at the Trans-Golgi Network. The authors demonstrate that the luminal domain of TGN46 is crucial for the incorporation of the soluble secretory protein PAUF into CARTS, a class of vesicles mediating TGN to surface traffic. The data presented are compelling, yielding a clear model for the sorting of cargos destined for secretion.

eLife assessment

This fundamental work substantially advances our understanding of how cells can tightly modulate small GTPase activity to build and maintain neighboring cytoskeletal structures, in this case microvilli. The evidence supporting these claims is compelling and is supported by both protein-protein interaction assays as well as cell biological studies. The work will be of interest to cell biologist studying the cytoskeleton as well as those interested in G-protein mediated regulation.

eLife assessment

This fundamental study provides insights into the mechanism controlling cell cycle reentry, establishing a regulatory role for Mecp2 degradation in shifting transcription from metabolic to proliferation genes during quiescence exit. The evidence, which includes experimental data from in vitro cell culture and an in vivo injury-induced liver regeneration model, is convincing but the trigger for MeCP2 degradation and how MeCP2 differentially regulates proliferation and metabolic genes remain unclear.

eLife assessment

This paper addresses a fundamental issue in the field of autophagy: how is a protein responsible for autophagosome-lysosome fusion recruited to mature autophagosomes but not immature ones? The work succeeds in its ambition to provide a new conceptual advance. The evidence supporting the conclusions is convincing, with fluorescence microscopy, biochemical assays, and molecular dynamics simulations. This work will be of broad interest to cell biologists and biochemists studying autophagy, and also those focusing on lipid/membrane biology.

eLife assessment

The study employs single-molecule tracking to provide-- albeit currently inadequate - evidence that a phosphosite (S938) previously identified in the immune receptor kinase FLS2 is required for its recruitment into nanodomains and for endocytosis after flg22 treatment. As this site is known to be essential for FLS2 signaling, the findings are potentially important and suggest a key role of phosphorylation-dependent nanodomain localization for FLS2 signaling.

eLife assessment

This valuable study provides solid evidence implicating two transcription factors in the development of the actin cytoskeleton that shapes the mechanosensory hair bundles of the inner ear's hair cells. The work will be of interest to biologists interested in the development and maintenance of the hair bundle, both normal or impaired. Its impact would be improved by providing a mechanistic model for the observed effects.

eLife assessment

These authors present a powerful tool to unbiasedly identify lysosome-associated proteins in C. elegans, and they provide a compelling, in-depth assessment of how this method can be used to understand longevity pathways and identify novel proteins. Understanding lysosomal differences in specific tissues or in response to different longevity conditions are exciting as it provides new insight into how organelles could control specific homeostasis responses. This valuable tool and proteomics datasets also represent a great resource for the C. elegans community and should pry open new studies on the regulation and role of the lysosome at the organismal level.

eLife assessment

In this study, the authors present important tools for monitoring distinct tissue-specific patterns of agonist-induced Free Fatty Acid receptor 2 phosphorylation. The work includes several validation experiments, which provide convincing evidence that will be beneficial for the scientific community.

eLife assessment

This study defines the roles for two different missense mutations observed in patients in the Trabid/ZRANB1 gene associated in children with a range of congenital disorders including reduced brain size. The study is important because the findings have theoretical or practical implications beyond a single subfield, as the study of DUB and cytoskeletal alterations have implications for neurodevelopment broadly. The methods are convincing as they utilize appropriate and validated methodology in line with current state-of-the-art by incorporating knock-in mice of the patient mutations. Many of the reviewer comments were focused on potential next experiments, rather than on evaluation of the data at hand, and the authors have considered these as future studies. The work as presented suggests critical roles for Trabid in the STRIPAK complex mediating APC deubiquitylation.

eLife assessment

This manuscript is an important advance in the study of Histone H1s, finding distinct distributions of various H1 variants in the genome. The controls presented by the authors provide convincing evidence to demonstrate a heterogenous distribution of H1 which might reflect functional regulation of chromatin accessibility by linker histones. This work will be of interest to the genome organization field, and could additionally provide a framework for understanding H1 mis-regulation observed in cancer cells.

eLife assessment

This paper investigates the potential role of extracellular vesicles in providing extracellular matrix signals for migration of vascular smooth muscle cells. The findings could be useful for researchers interested in cell migration, but the evidence supporting the conclusions is presently incomplete.