Stress granules (SGs) are condensed membrane-less organelles that form dynamically as RNA and protein (RNP) phase separate during physiological stress. When translation initiation is limited, SGs assemble and play a role in translational regulation and proteome buffering. Translationally stalled mRNAs, translation initiation factors, RNA-binding proteins, and non-RNA-binding proteins are among the constituents of SGs. SGs are one of the most important cellular stress relievers, yet their presence are temporary. Any condition that causes permanent presence of SGs, such as chronic stress or alterations in the structure of the components of SGs, can induce their pathological aggregation and degenerative effects (31626750, 26777405, 29373831, 34248597, 30326201).
Formation, Composition & dynamics (Assembly and disassembly)
Relation to human diseases
Proteome
Formation, Composition & dynamics of (Assembly and disassembly)
SGs are composed of two subcompartments, a core and a shell. Cores are densely packed areas of mRNAs and proteins surrounding by a less dense shell, which is thought to be more dynamic. The development of SGs has been proposed as a two-step process, with the dense stable core being formed first, followed by the accumulation of proteins with intrinsically disordered regions (IDRs) and low-complexity domains (LCDs) into the peripheral shell via liquid-liquid phase separation (LLPS). Stress, viral infection, and signal transduction all trigger SG production, and abnormal SG assembly can lead to tissue degeneration. SGs are mRNA and protein assemblies formed by mRNAs that have halted in translation initiation as a result of stress. The type of stress, length of stress, cell type, and cellular location have all been found to affect the protein and RNA composition of SGs. Chronic stress and aberrant assembly or disassembly of these granules have pathological implications in cancer, viral infection and neurodegeneration (29373831, 34170048, 34095105, 32873715)
18794846 used an RNA-mediated interference-based screen, and identified 101 human genes required for SG assembly and many other genes coordinating their assembly. Moreover, 26777405 showed that ATP is required for stress granule assembly and dynamics with the Chaperonin- Containing T complex (CCT complex) inhibiting stress granule assembly, while the MCM and RVB helicase complexes promote stress granule persistence.
In addition, emerging evidence has shown that small molecules can affect SG dynamics, making them potential therapeutic molecules targeting SGs for the treatment of human diseases. The effects of small molecules on SG assembly, disassembly, and their roles in the disease is described in the literature (32814168).
(34095105, 30082464, 32500266).
Relation to human diseases
Stress granule (SG) are associated with mRNA turnover and protection of mRNA during stress conditions. Given the varied effects that RNA granules have on metabolism and cell signaling, it is not surprising that SGs are also implicated in many diseases. Defects in SG dynamics are found in cancer, neurodegenerative disease, viral infection, and autoimmune disease. Several recent studies and reviews discuss in detail the roles that RNA granules play in disease pathogenesis (30082464, 34248597, 29373831, 26777405, 32814168, 32500266). 32814168 and 34170048 thoroughly describe SGs in cancer, viral infection, aging, neurodegeneration, inflammation and germ cell development.
Proteome
While SGs have long been known to contain RNA and protein, the exact RNA and protein composition of these assemblies has remained enigmatic due to lack of suitable purification techniques. Recently, different methodologies were used to elucidate the transcriptomes of these granules and several studies have addressed the issues of the purification and analysis of SGs.
31626750 created an RNA granule database (RNAgranuleDB), which is available at http://rnagranuledb. lunenfeld.ca. Through this website, users can find an updated and manually curated matrix of evidence from the primary literature supporting whether a protein resides in SGs or PBs, alongside a cumulative confidence score and protein feature analysis. This provides a comprehensive summary of SG and PB components.
29373831 analysed the proteome and compositional diversity of SGs in different cell types and in the context of neurodegeneration linked mutations and the combination of ascorbate peroxidase (APEX)-mediated in vivo proximity labeling with quantitative mass spectrometry (MS) and an RBP-focused immunofluorescence (IF) approach to comprehensively and significantly expand the repertoire of known SG proteins across different cell types, stress conditions, and disease states.
32105731 compiled recently published stress granule composition data, formed specifically through heat and oxidative stress, for both mammalian (Homo sapiens) and yeast (Saccharomyces cerevisiae) cells.
26777405 purified mammalian stress granule cores from Sodium Arsenite (NaAsO2) stressed U-2 OS cells using a series of differential centrifugations and then affinity purification of GFP G3BP. The study used mass spectrometry and immunofluorescence (IF) to identify proteins and validate their localization.
30082464 and 31591142 might be useful sources comparing SG and PB in transcriptome and translational control.
References
Youn JY, Dyakov BJA, Zhang J, Knight JDR, Vernon RM, Forman-Kay JD, Gingras AC. Properties of Stress Granule and P-Body Proteomes. Mol Cell. 2019 Oct 17;76(2):286-294. doi: 10.1016/j.molcel.2019.09.014. PMID: 31626750.
Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, Parker R. ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell. 2016 Jan 28;164(3):487-98. doi: 10.1016/j.cell.2015.12.038. Epub 2016 Jan 14. PMID: 26777405; PMCID: PMC4733397.
Markmiller S, Soltanieh S, Server KL, Mak R, Jin W, Fang MY, Luo EC, Krach F, Yang D, Sen A, Fulzele A, Wozniak JM, Gonzalez DJ, Kankel MW, Gao FB, Bennett EJ, Lécuyer E, Yeo GW. Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules. Cell. 2018 Jan 25;172(3):590-604.e13. doi: 10.1016/j.cell.2017.12.032. PMID: 29373831; PMCID: PMC5969999.
Asadi MR, Sadat Moslehian M, Sabaie H, Jalaiei A, Ghafouri-Fard S, Taheri M, Rezazadeh M. Stress Granules and Neurodegenerative Disorders: A Scoping Review. Front Aging Neurosci. 2021 Jun 23;13:650740. doi: 10.3389/fnagi.2021.650740. PMID: 34248597; PMCID: PMC8261063.
Reineke LC, Neilson JR. Differences between acute and chronic stress granules, and how these differences may impact function in human disease. Biochem Pharmacol. 2019 Apr;162:123-131. doi: 10.1016/j.bcp.2018.10.009. Epub 2018 Oct 14. PMID: 30326201; PMCID: PMC6421087.
Wang L, Yang W, Li B, Yuan S, Wang F. Response to stress in biological disorders: Implications of stress granule assembly and function. Cell Prolif. 2021 Aug;54(8):e13086. doi: 10.1111/cpr.13086. Epub 2021 Jun 25. PMID: 34170048; PMCID: PMC8349659.
Campos-Melo D, Hawley ZCE, Droppelmann CA, Strong MJ. The Integral Role of RNA in Stress Granule Formation and Function. Front Cell Dev Biol. 2021 May 20;9:621779. doi: 10.3389/fcell.2021.621779. PMID: 34095105; PMCID: PMC8173143.
Riggs CL, Kedersha N, Ivanov P, Anderson P. Mammalian stress granules and P bodies at a glance. J Cell Sci. 2020 Sep 1;133(16):jcs242487. doi: 10.1242/jcs.242487. PMID: 32873715.
Ohn T, Kedersha N, Hickman T, Tisdale S, Anderson P. A functional RNAi screen links O-GlcNAc modification of ribosomal proteins to stress granule and processing body assembly. Nat Cell Biol. 2008 Oct;10(10):1224-31. doi: 10.1038/ncb1783. Epub 2008 Sep 14. PMID: 18794846; PMCID: PMC4318256.
Wang F, Li J, Fan S, Jin Z, Huang C. Targeting stress granules: A novel therapeutic strategy for human diseases. Pharmacol Res. 2020 Nov;161:105143. doi: 10.1016/j.phrs.2020.105143. Epub 2020 Aug 16. PMID: 32814168; PMCID: PMC7428673.
Campos-Melo D, Hawley ZCE, Droppelmann CA, Strong MJ. The Integral Role of RNA in Stress Granule Formation and Function. Front Cell Dev Biol. 2021 May 20;9:621779. doi: 10.3389/fcell.2021.621779. PMID: 34095105; PMCID: PMC8173143.
Ivanov P, Kedersha N, Anderson P. Stress Granules and Processing Bodies in Translational Control. Cold Spring Harb Perspect Biol. 2019 May 1;11(5):a032813. doi: 10.1101/cshperspect.a032813. PMID: 30082464; PMCID: PMC6496347.
Advani VM, Ivanov P. Stress granule subtypes: an emerging link to neurodegeneration. Cell Mol Life Sci. 2020 Dec;77(23):4827-4845. doi: 10.1007/s00018-020-03565-0. Epub 2020 Jun 4. PMID: 32500266; PMCID: PMC7668291.
Ivanov P, Kedersha N, Anderson P. Stress Granules and Processing Bodies in Translational Control. Cold Spring Harb Perspect Biol. 2019 May 1;11(5):a032813. doi: 10.1101/cshperspect.a032813. PMID: 30082464; PMCID: PMC6496347.
Kuechler ER, Budzyńska PM, Bernardini JP, Gsponer J, Mayor T. Distinct Features of Stress Granule Proteins Predict Localization in Membraneless Organelles. J Mol Biol. 2020 Mar 27;432(7):2349-2368. doi: 10.1016/j.jmb.2020.02.020. Epub 2020 Feb 24. PMID: 32105731.
Matheny T, Rao BS, Parker R. Transcriptome-Wide Comparison of Stress Granules and P-Bodies Reveals that Translation Plays a Major Role in RNA Partitioning. Mol Cell Biol. 2019 Nov 25;39(24):e00313-19. doi: 10.1128/MCB.00313-19. PMID: 31591142; PMCID: PMC6879202.