A New Phase of Networking: The Molecular Composition and Regulatory Dynamics of Mammalian Stress Granules

Abstract

Stress granules (SGs) are cytosolic biomolecular condensates that form in response to cellular stress. Weak, multivalent interactions between their protein and RNA constituents drive their rapid, dynamic assembly through phase separation coupled to percolation. Though a consensus model of SG function has yet to be determined, their perceived implication in cytoprotective processes ( e.g. , antiviral responses and inhibition of apoptosis) and possible role in the pathogenesis of various neurodegenerative diseases ( e.g. , amyotrophic lateral sclerosis and frontotemporal dementia) have drawn great interest. Consequently, new studies using numerous cell biological, genetic, and proteomic methods have been performed to unravel the mechanisms underlying SG formation, organization, and function and, with them, a more clearly defined SG proteome. Here, we provide a consensus SG proteome through literature curation and an update of the user-friendly database RNAgranuleDB to version 2.0 (). With this updated SG proteome, we use next-generation phase separation prediction tools to assess the predisposition of SG proteins for phase separation and aggregation. Next, we analyze the primary sequence features of intrinsically disordered regions (IDRs) within SG-resident proteins. Finally, we review the protein- and RNA-level determinants, including post-translational modifications (PTMs), that regulate SG composition and assembly/disassembly dynamics.

Graphene Transistors for In Vitro Detection of Health Biomarkers

“…[116] Copyright 2020, Elsevier B.V. sample-to-answer time of <15 min, indicating its great promise for POC diagnosis applications. [121,204]…”

“…[98,[203][204][205] Among these diseases, AD is a widely investigated neurodegenerative disease that accounts for 70% of all dementia and affects the quality of human life. [203][204][205] Early diagnosis of AD is of vital importance because there is no certain treatment after the lesion has progressed in the late stage. [116,203] In 2020, Park et al demonstrated a dualantibody-modified GFET biosensor for multiplex detection of two AD biomarkers (Figure 11a).…”

“…[ 121 ] Compared with commercial ELISA kits and single‐molecule array (Simoa) technology, the proposed GFET approach exhibited competitive LoD down to 231 fg mL −1 and a short sample‐to‐answer time of <15 min, indicating its great promise for POC diagnosis applications. [ 121,204 ]…”

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

“…The current studies reveal a likely interaction between native C9orf72 protein and PRMTs in regulating these pathways in C9orf72-mutation-mediated neurodegeneration. Recent studies have highlighted the importance of stress granule formation and requisite liquid-liquid phase separation as modulators of C9orf72 mutation-mediated cytotoxicity in cell-based models ( Liu et al, 2023 ; Millar et al, 2023 ). For example, C9orf72 has been demonstrated to be a regulator of the integrated stress response (ISR), facilitating stimulation of the unfolded protein response (UPR), inhibition of stress granule formation, and LLPS through interaction with eIF2a ( Zheng et al, 2022 ).…”

C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1

“…The stress granule (SG) proteome was obtained from RNAGranuleDB [55] by taking only Tier 1 SG proteins. The nucleolar proteome was derived from [56], by only accepting proteins with "Enhanced" or "Supported" nucleolar localization to gain a high-confidence dataset.…”