TRIM25 Predominately Associates with Anti-viral Stress Granules

Overview

Journal Nat Commun

Specialty Biology

Date 2024 May 15

PMID 38750080

Authors

Zehua Shang

Sitao Zhang

Jinrui Wang

Lili Zhou

Xinyue Zhang

Daniel D Billadeau

Peiguo Yang

Lingqiang Zhang

Fangfang Zhou

Peng Bai

Da Jia

Affiliations

Soon will be listed here.

Abstract

Stress granules (SGs) are induced by various environmental stressors, resulting in their compositional and functional heterogeneity. SGs play a crucial role in the antiviral process, owing to their potent translational repressive effects and ability to trigger signal transduction; however, it is poorly understood how these antiviral SGs differ from SGs induced by other environmental stressors. Here we identify that TRIM25, a known driver of the ubiquitination-dependent antiviral innate immune response, is a potent and critical marker of the antiviral SGs. TRIM25 undergoes liquid-liquid phase separation (LLPS) and co-condenses with the SG core protein G3BP1 in a dsRNA-dependent manner. The co-condensation of TRIM25 and G3BP1 results in a significant enhancement of TRIM25's ubiquitination activity towards multiple antiviral proteins, which are mainly located in SGs. This co-condensation is critical in activating the RIG-I signaling pathway, thus restraining RNA virus infection. Our studies provide a conceptual framework for better understanding the heterogeneity of stress granule components and their response to distinct environmental stressors.

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References

Heikel G, Choudhury N, Michlewski G . The role of Trim25 in development, disease and RNA metabolism. Biochem Soc Trans. 2016; 44(4):1045-50. DOI: 10.1042/BST20160077. View

Li M, Lau Z, Cheung P, Aguilar E, Schneider W, Bozzacco L . TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP). PLoS Pathog. 2017; 13(1):e1006145. PMC: 5245905. DOI: 10.1371/journal.ppat.1006145. View

Aulas A, Fay M, Lyons S, Achorn C, Kedersha N, Anderson P . Stress-specific differences in assembly and composition of stress granules and related foci. J Cell Sci. 2017; 130(5):927-937. PMC: 5358336. DOI: 10.1242/jcs.199240. View

Gack M, Kirchhofer A, Shin Y, Inn K, Liang C, Cui S . Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated antiviral signal transduction. Proc Natl Acad Sci U S A. 2008; 105(43):16743-8. PMC: 2575490. DOI: 10.1073/pnas.0804947105. View

Portz B, Lee B, Shorter J . FUS and TDP-43 Phases in Health and Disease. Trends Biochem Sci. 2021; 46(7):550-563. PMC: 8195841. DOI: 10.1016/j.tibs.2020.12.005. View

Gao Y, Li X, Li P, Lin Y . A brief guideline for studies of phase-separated biomolecular condensates. Nat Chem Biol. 2022; 18(12):1307-1318. DOI: 10.1038/s41589-022-01204-2. View

Eiermann N, Haneke K, Sun Z, Stoecklin G, Ruggieri A . Dance with the Devil: Stress Granules and Signaling in Antiviral Responses. Viruses. 2020; 12(9). PMC: 7552005. DOI: 10.3390/v12090984. View

Zhao M, Xia T, Xing J, Yin L, Li X, Pan J . The stress granule protein G3BP1 promotes pre-condensation of cGAS to allow rapid responses to DNA. EMBO Rep. 2021; 23(1):e53166. PMC: 8728604. DOI: 10.15252/embr.202153166. View

Choudhury N, Heikel G, Trubitsyna M, Kubik P, Nowak J, Webb S . RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC Biol. 2017; 15(1):105. PMC: 5678581. DOI: 10.1186/s12915-017-0444-9. View

10.

Guan Y, Wang Y, Fu X, Bai G, Li X, Mao J . Multiple functions of stress granules in viral infection at a glance. Front Microbiol. 2023; 14:1138864. PMC: 10014870. DOI: 10.3389/fmicb.2023.1138864. View

11.

Yang E, Huang S, Jami-Alahmadi Y, McInerney G, Wohlschlegel J, Li M . Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes. PLoS Pathog. 2022; 18(9):e1010743. PMC: 9481182. DOI: 10.1371/journal.ppat.1010743. View

12.

Manjunath L, Oh S, Ortega P, Bouin A, Bournique E, Sanchez A . APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection. Nat Commun. 2023; 14(1):820. PMC: 9925369. DOI: 10.1038/s41467-023-36445-9. View

13.

Kato K, Ahmad S, Zhu Z, Young J, Mu X, Park S . Structural analysis of RIG-I-like receptors reveals ancient rules of engagement between diverse RNA helicases and TRIM ubiquitin ligases. Mol Cell. 2020; 81(3):599-613.e8. PMC: 8183676. DOI: 10.1016/j.molcel.2020.11.047. View

14.

Yang Y, Luo Y, Yang C, Hu R, Qin X, Li C . TRIM25-mediated ubiquitination of G3BP1 regulates the proliferation and migration of human neuroblastoma cells. Biochim Biophys Acta Gene Regul Mech. 2023; 1866(3):194954. DOI: 10.1016/j.bbagrm.2023.194954. View

15.

Gack M, Shin Y, Joo C, Urano T, Liang C, Sun L . TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature. 2007; 446(7138):916-920. DOI: 10.1038/nature05732. View

16.

Zheng Z, Wang S, Xu Z, Fu Y, Wang Y . SARS-CoV-2 nucleocapsid protein impairs stress granule formation to promote viral replication. Cell Discov. 2021; 7(1):38. PMC: 8147577. DOI: 10.1038/s41421-021-00275-0. View

17.

Song D, Kuang L, Yang L, Wang L, Li H, Li X . Yin and yang regulation of stress granules by Caprin-1. Proc Natl Acad Sci U S A. 2022; 119(44):e2207975119. PMC: 9636964. DOI: 10.1073/pnas.2207975119. View

18.

Anderson P, Kedersha N . RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat Rev Mol Cell Biol. 2009; 10(6):430-6. DOI: 10.1038/nrm2694. View

19.

Marmor-Kollet H, Siany A, Kedersha N, Knafo N, Rivkin N, Danino Y . Spatiotemporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis. Mol Cell. 2020; 80(5):876-891.e6. PMC: 7816607. DOI: 10.1016/j.molcel.2020.10.032. View

20.

Burke J, Moon S, Matheny T, Parker R . RNase L Reprograms Translation by Widespread mRNA Turnover Escaped by Antiviral mRNAs. Mol Cell. 2019; 75(6):1203-1217.e5. PMC: 6754297. DOI: 10.1016/j.molcel.2019.07.029. View