bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.10.19.344929

Cyclase-associated protein 2 (CAP2) controls MRTF-A localization and SRF activity in mouse embryonic fibroblasts

Kepser, L.-J.·Hinojosa, L. S.·Macchi, C.·Ruscica, M.·Marcello, E.·Culmsee, C.·Grosse, R.·Rust, M. B.
View original source ↗Export metadata ↓

Abstract

Recent studies identified cyclase-associated proteins (CAPs) as important regulators of actin dynamics that control assembly and disassembly of actin filaments (F-actin). While these studies significantly advanced our knowledge of their molecular functions, the physiological relevance of CAPs largely remained elusive. Gene targeting in mice implicated CAP2 in heart physiology and skeletal muscle development. Heart defects in CAP2 mutant mice were associated with altered activity of serum response factor (SRF), a transcription factor involved in multiple biological processes including heart function, but also skeletal muscle development. By exploiting mouse embryonic fibroblasts (MEFs) from CAP2 mutant mice, we aimed at deciphering the CAP2-dependent mechanism relevant for SRF activity. Reporter assays and mRNA quantification by qPCR revealed reduced SRF-dependent gene expression in mutant MEFs. Reduced SRF activity was associated with moderately increased G-actin levels and reduced nuclear levels of MRTF-A, a transcriptional SRF coactivator that is shuttled out of the nucleus and, hence, inhibited upon G-actin binding. Moreover, pharmacological actin manipulation restored MRTF-A distribution in mutant MEFs. Our data are in line with a model in which CAP2 controls the MRTF-SRF pathway in an actin-dependent manner. While MRTF-A localization and SRF activity was impaired under basal conditions, serum stimulation induced nuclear MRTF-A translocation and SRF activity in mutant MEFs similar to controls. In summary, our data revealed that in MEFs CAP2 controls basal MRTF-A localization and SRF activity, while it was dispensable for serum-induced nuclear MRTF-A translocation and SRF stimulation.

Source connections

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Kepser, L.-J., Hinojosa, L. S., Macchi, C., Ruscica, M., Marcello, E., Culmsee, C., Grosse, R., Rust, M. B.. 2020-10-19. Cyclase-associated protein 2 (CAP2) controls MRTF-A localization and SRF activity in mouse embryonic fibroblasts. https://doi.org/10.1101/2020.10.19.344929

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

RCDome: A Multi-Database Human Gene Atlas of Regulated Cell Death

Introduction: Regulated cell death (RCD) governs tissue homeostasis, development, and disease, and is executed or regulated by specific genes. Yet for the researcher asking which genes execute or regulate a given RCD form, the answer is rarely simple: gene lists for the same form rarely agree across databases, many associations carry no traceable source, and most have never been systematically checked against primary literature. We built RCDome to answer the most basic question a researcher can ask: where did this gene-RCD association come from, and what is the evidence? Methods: RCDome is a multi-database human gene atlas built through a staged architecture integrating multi-source compilation, literature validation and evidence recovery, mechanistic classification, human-governed ontological adjudication, and web deployment. Five complementary evidence channels (PubMed Boolean search, curated databases, AI-assisted screening, manual curation, and Elicit systematic review) were integrated from 20 public databases into a unified matrix. Sixty-two original name strings were canonicalized into 53 RCD-related entities with curator-adjudicated operational definitions and ontological levels. Gene-RCD associations were systematically evaluated through an independent DeepSeek two-call LLM validation, Europe PMC full-text recovery and deep evidence extraction, an independent Consensus literature-search channel, and GPT-4o arbitration of disagreements. Source-grounding controls rejected extracted evidence not found verbatim in the source document, while the governance contract was enforced as executable code. Results: The compendium holds 22,473 association rows spanning 9,265 unique HGNC-validated genes (21,568 unique gene-RCD pairs). Evidence-first adjudication resolved 5,138 pairs (23.8%) as mechanistically involved; across the 4,775 role-resolved pairs, 225 (4.7%) are executors, 4,455 (93.3%) are regulators, and 95 are markers, revealing a small death-executing core embedded in a vast regulatory network. Under a separate seven-class mechanistic criterion applied to all 22,473 rows, only 3,063 (13.6%) were mechanistically confirmed and 286 (1.3%) were database-only with no verifiable paper trail. Conclusion: RCDome makes the RCD evidence landscape measurable and traceable, showing that AI-assisted curation can be verifiable, human-governed, and explicit about uncertainty. It is delivered as a Shiny web application that lets any researcher query the atlas and inspect the evidence behind each association. Availability: RCDome is freely available at https://rcdome.org/ (source code and data at https://github.com/BioCancerInformatics/RCDome).

cell biology↗
bioRxiv2026

Circadian Clock Coordination of the Notch-to-Wnt Signaling Switch Promotes Regenerative Myogenesis

Regenerative deficits of muscle stem cells (MuSCs) contribute to progressive muscle loss in muscular dystrophy. Successful regenerative repair requires a Notch to Wnt switch to allow MuSC expansion and myogenic differentiation, yet the underlying mechanisms remain poorly understood. Leveraging complementary genetic and pharmacological approaches, here we identify the circadian clock as a key regulator of the Notch to Wnt signaling transition to promote regeneration with therapeutic potential for dystrophic disease. Circadian clock activity marks cycling myogenic progenitors during muscle regeneration, and clock induction occurs in concert with Notch activation. We identify that key components of the Notch pathway are direct transcriptional targets of the clock that were induced by clock activation. Mechanistically, clock coordination of Notch and Wnt signaling promoted MuSC proliferative expansion while facilitating myogenic progression during regeneration. Importantly, this clock-regulated mechanism was preserved in dystrophin-deficient mouse and human myoblasts, and clock-activating compounds enhanced regenerative myogenesis in dystrophic muscle. Collectively, our findings uncover a circadian clock-controlled mechanism that orchestrates regenerative signaling transition with potential for therapeutic targeting to restore regenerative capacity in dystrophic disease.

cell biology↗
bioRxiv2026

The yeast Gcn2 protein kinase mediates P-body formation both through its activity with eIF2α and with non-canonical substrates

P-bodies (PBs) are control hubs for RNA processing and storage that form when translation initiation is inhibited, including during stress. In yeast, Gcn2 is the sole eIF2 alpha kinase that inhibits translation initiation in response to diverse stresses. We show that PB formation depends strongly on Gcn2 during amino acid starvation but only partially during oxidative stress. Constitutively active Gcn2 also induces PB formation in unstressed cells. Surprisingly, PBs are still constitutively formed in a gcn3 mutant strain that is insensitive to eIF2 alpha phosphorylation suggesting that Gcn2 also promotes PB formation independently of eIF2 alpha phosphorylation. Analysis of several putative Gcn2-substrates involved in RNA metabolism identified several proteins required for Gcn2-mediated PB formation. Among these, Smu2, which was not previously implicated in PB formation, localises to PBs and is required for stress-induced coalescence of mRNA granules into PBs. Together, our findings indicate that Gcn2 promotes PB formation via two complementary routes: eIF2 alpha phosphorylation, which generates untranslated mRNAs, and Smu2-dependent maturation of mRNA granules into PBs.

cell biology↗