Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules

Autophagy, Journal Year: 2023, Volume and Issue: 19(7), P. 1934 - 1951

Published: Jan. 24, 2023

Eukaryotic stress granules (SGs) are highly dynamic assemblies of untranslated mRNAs and proteins that form through liquid-liquid phase separation (LLPS) under cellular stress. SG formation elimination process is a conserved strategy to promote cell survival, although the precise regulation this poorly understood. Here, we screened six E3 ubiquitin ligases present in SGs identified TRIM21 (tripartite motif containing 21) as central regulator homeostasis enriched cells arsenite-induced oxidative Knockdown promotes whereas overexpression inhibits physiological pathological associated with neurodegenerative diseases. catalyzes K63-linked ubiquitination core protein, G3BP1 (G3BP granule assembly factor 1), can effectively inhibit LLPS, vitro. Recent reports suggested involvement macroautophagy/autophagy, response pathway, homeostasis. We systematically investigated well-defined autophagy receptors SQSTM1/p62 (sequestosome 1) CALCOCO2/NDP52 (calcium binding coiled-coil domain 2) primary directly interact during Endogenous SQSTM1 CALCOCO2 localize periphery mediate elimination, single knockout each receptor causes accumulation SGs. Collectively, our study broadens understanding by showing modulate respectively, suggesting possibility clinical targeting these molecules therapeutic strategies for

Language: Английский

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SAMHD1 Functions and Human Diseases

Viruses, Journal Year: 2020, Volume and Issue: 12(4), P. 382 - 382

Published: March 31, 2020

Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells a variety viral pathogens. While process dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) thymidine kinase (TK), has been extensively investigated, negative regulatory mechanism pools was recently found to involve sterile alpha motif (SAM) domain histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, triphosphohydrolase activity SAMHD1 degrades dNTPs into their 2'-deoxynucleoside (dN) subparts, steadily depleting intercellular pools. The differential expression levels activation states various cell types contributes unique that either aid (i.e., dividing T cells) or restrict nondividing macrophages) consumes dNTPs. Genetic mutations induce rare inflammatory encephalopathy called Aicardi-Goutières syndrome (AGS), which phenotypically resembles infection. Recent publications have identified diverse roles double-stranded break repair, genome stability, stress response through interferon signaling. Finally, series were also reported cancer while why is mutated these remains investigated. Here, we reviewed studies begun illuminating highly virology, immunology, biology.

Language: Английский

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TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 6, 2021

TRIM21 (Ro52/SSA1) is an E3 ubiquitin ligase with key roles in immune host defence, signal transduction, and possibly cell cycle regulation. It also autoantibody target Sjögren's syndrome, systemic lupus erythematosus, other rheumatic autoimmune diseases. Here, we summarise the structure function of this enzyme, its innate immunity, adaptive immunity cellular homeostasis, pathogenesis autoimmunity against TRIM21, potential impacts autoantibodies to intracellular protein.

Language: Английский

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Trim21-mediated HIF-1α degradation attenuates aerobic glycolysis to inhibit renal cancer tumorigenesis and metastasis

Cancer Letters, Journal Year: 2021, Volume and Issue: 508, P. 115 - 126

Published: March 29, 2021

Language: Английский

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TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity

EMBO Reports, Journal Year: 2019, Volume and Issue: 21(1)

Published: Dec. 4, 2019

Abstract SAMHD 1 possesses multiple functions, but whether cellular factors regulate expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK 293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that is a restriction factor for EV71. Importantly, identify TRIM 21, an E3 ubiquitin ligase, as key regulator of 1, which specifically interacts degrades through the proteasomal pathway. However, 21 has no effect on EV71 replication itself. Moreover, prove interferon production stimulated infection induces increased expression, whereas increasing overrides inhibition in neonatal mouse model. 21‐mediated degradation also affects 1‐dependent HIV ‐1 regulation production. We further functional domains required binding ubiquitination site K622 phosphorylation at T592 blocks restriction. Our findings illuminate how overcomes via upregulation 21.

Language: Английский

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TRIM21 attenuates renal carcinoma lipogenesis and malignancy by regulating SREBF1 protein stability

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Jan. 25, 2023

Metabolic reprogramming is a hallmark of various cancers. Targeting metabolic processes very attractive treatment for cancer. Renal cell carcinoma (RCC) type disease, and the lipidomic profile RCC significantly altered compared with that healthy tissue. However, molecular mechanism underlying lipid metabolism regulation in not clear.The XF long-chain fatty acid oxidative stress test kits were used to assess dependence on acids mitochondrial function after knockdown TRIM21 cells. The effect content cells was determined by metabolomics analysis, Oil Red O staining, cellular Nile red staining. qRT-PCR western blot explore relationship between lipogenesis, then key molecule sterol regulatory element binding transcription factor 1 (SREBF1) identified interact immunoprecipitation, which also an orthotopic model. Subsequently, relevance clinical significance SREBF1 analyzed Cancer Genome Atlas (TCGA) database, 239 tissues collected from patients.TRIM21 silencing attenuated acids, enhanced accumulation overexpression decreased contents decreasing expression lipogenic enzymes via ubiquitination-mediated degradation SREBF1. critical TRIM21-mediated lipogenesis inhibition vitro vivo. Moreover, negatively correlated expression, TRIM21-SREBF1 reliable combinational biomarker prognosis.The findings this study reveal novel pathway through inhibits process shed light development targeted prognosis diagnosis RCC.

Language: Английский

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Multiple Roles of TRIM21 in Virus Infection

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1683 - 1683

Published: Jan. 14, 2023

The tripartite motif protein 21 (TRIM21) belongs to the TRIM family, possessing an E3 ubiquitin ligase activity. Similar other TRIMs, TRIM21 also contains three domains (named RBCC), including Really Interesting New Gene (RING) domain, one or two B-Box (B-Box), and PRY/SPRY domain. Notably, we found that RING are relatively more conservative than suggesting of different species had similar functions. Recent results showed participates in virus infection by directly interacting with viral proteins modulating immune inflammatory responses. acts as a cytosol high-affinity antibody Fc receptor, binding antibody–virus complex triggering indirect antiviral antibody-dependent intracellular neutralization (ADIN). This paper focuses on recent progress mechanism during application prospects infection.

Language: Английский

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Hexosamine biosynthetic pathway promotes the antiviral activity of SAMHD1 by enhancing O-GlcNAc transferase-mediated protein O-GlcNAcylation

Theranostics, Journal Year: 2020, Volume and Issue: 11(2), P. 805 - 823

Published: Nov. 6, 2020

Rationale:Viruses hijack the host cell machinery to promote viral replication; however, mechanism by which metabolic reprogramming regulates innate antiviral immunity in remains elusive.Herein, we explore how hexosamine biosynthesis pathway (HBP) and O-linked-N-acetylglucosaminylation (O-GlcNAcylation) regulate response against hepatitis B virus (HBV) vitro vivo.Methods: We conducted a metabolomics assay evaluate responses of cells HBV infection.We systematically explored role HBP protein O-GlcNAcylation regulating infection mouse models.O-linked N-acetylglucosamine (O-GlcNAc) target proteins were identified via liquid chromatography-tandem mass spectrometry (LC-MS) co-immunoprecipitation assays.Additionally, also examined uridine diphosphate (UDP)-GlcNAc levels patients with chronic (CHB).Results: upregulated GLUT1 expression on hepatocyte surface facilitated glucose uptake, provides substrates synthesize UDP-GlcNAc, leading an increase O-GlcNAcylation.Pharmacological or transcriptional inhibition promoted replication.Mechanistically, O-GlcNAc transferase (OGT)-mediated sterile alpha motif histidine/aspartic acid domain-containing 1 (SAMHD1) Ser93 stabilizes SAMHD1 enhances its activity.Analysis clinical samples revealed that UDP-GlcNAc level was increased, O-GlcNAcylated CHB.Conclusions: HBP-mediated positively vivo.The findings reveal link between HBP, modification, targeting SAMHD1.

Language: Английский

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De-ubiquitination of SAMHD1 by USP7 promotes DNA damage repair to overcome oncogenic stress and affect chemotherapy sensitivity

Oncogene, Journal Year: 2023, Volume and Issue: 42(22), P. 1843 - 1856

Published: April 20, 2023

Abstract Oncogenic stress induces DNA damage repair (DDR) that permits escape from mitotic catastrophe and allows early precursor lesions during the evolution of cancer. SAMHD1, a dNTPase protecting cells viral infections, has been recently found to participate in process. However, its role tumorigenesis remains largely unknown. Here, we show SAMHD1 is up-regulated early-stage human carcinoma tissues cell lines under oxidative or genotoxic insults. We further demonstrate de-ubiquitinating enzyme USP7 interacts with de-ubiquitinates it at lysine 421, thus stabilizing protein expression for interaction CtIP DDR, which promotes tumor survival stress. Furthermore, levels positively correlates various carcinomas, associated an unfavorable outcome patients who underwent chemotherapy. Moreover, inhibitor sensitizes chemotherapeutic agents by decreasing vitro vivo. These findings suggest de-ubiquitination DDR overcome oncogenic affect chemotherapy sensitivity.

Language: Английский

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Type I interferon/STAT1 signaling regulates UBE2M-mediated antiviral innate immunity in a negative feedback manner

Cell Reports, Journal Year: 2023, Volume and Issue: 42(1), P. 112002 - 112002

Published: Jan. 1, 2023

Type I interferon (IFN-I) signaling is central to inducing antiviral innate immunity. However, the mechanisms for IFN-I self-regulation are still largely unknown. Here, we report that RNA virus-infected macrophages with UBE2M deficiency produced decreased expression in a RIG-I-dependent manner, causing an aggravated viral infection. Mechanistically, inhibits RIG-I degradation by preventing interaction of and E3 ligase STUB1, resulting activation. Simultaneously, signaling-activated STAT1 facilitates transcription Trim21, leading increased blunted Translationally, oral administration milk-derived extracellular vesicles containing RING domain-truncated TRIM21 (TRIM21-ΔRING) lacking activity efficiently transfers TRIM21-ΔRING into macrophages. suppresses competitively binding TRIM21, thereby enhancing Overall, reveal negative feedback loop develop reagent improve immunity against viruses.

Language: Английский

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