TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease

Jones, Eric J.; Laidlaw, Stephen M.; Dustin, Lynn B.

doi:10.3389/fimmu.2021.738473

Cited by 51 publications

(45 citation statements)

References 187 publications

(246 reference statements)

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“…E3 ligases are vital components in this process, directly interacting with and catalyzing different ubiquitin linkages of their specific substrates, which can occur through K6-, K11-, K27-, K29-, K33-, K48- and K63-linked ubiquitination (Cruz Walma DA et al, 2022). Several types of ubiquitin linkages catalyzed by TRIM21 have been reported, and different ubiquitin linkages play distinct roles in host defense against pathogenic invasion (Jones EL et al, 2021). For instance, TRIM21-mediated K48-linked ubiquitination is tightly related to proteasome-dependent degradation, which results in the degradation of viral proteins in virus-infected cells (Mu T et al, 2020, Song Y et al, 2021, Hauler F et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Several types of ubiquitin linkages catalyzed by TRIM21 have been reported, and different ubiquitin linkages play distinct roles in host defense against pathogenic invasion (Jones EL et al, 2021). For instance, TRIM21-mediated K48-linked ubiquitination is tightly related to proteasome-dependent degradation, which results in the degradation of viral proteins in virus-infected cells (Mu T et al, 2020, Song Y et al, 2021, Hauler F et al, 2012.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of protein translation by TRIM21

Liu

et al. 2022

Preprint

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Regulation of translation initiation is essential for maintenance of protein homeostasis and typically involves the phosphorylation of translation initiation factor eIF2? in eukaryotes. In response to stressors, cells employ eIF2α-dependent signaling to control translation initiation. We focus on the role of TRIM21 in the regulation of protein translation mediated by PKR which phosphorylates eIF2α. TRIM21 deficiency enhances PKR activation. TRIM21 interacts with PKR, and the E3 ligase activity of TRIM21 is crucial for stress-triggered PKR inactivation. TRIM21 interacts with the PKR phosphatase PP1α and promotes K6-linked polyubiquitination of PP1α. Ubiquitination of PP1α augments its interaction with PKR, causing PKR inactivation and subsequent dephosphorylation of eIF2α, initiating protein synthesis. Moreover, TRIM21 constitutively restricts viral infection by reversing PKR-mediated inhibition of the protein synthesis of intrinsic antiviral genes. The TRIM21-PP1α axis acts as a newly discovered program that regulates PKR-associated protein synthesis and broadens our knowledge of antiviral genes. Moreover, TRIM21-mediated regulation of PKR activation provides evidence that TRIM21 may anticipate the interferon-dependent immunotherapy. Our study highlights the essential role of TRIM21 in regulating protein translation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of protein translation by TRIM21

Liu

et al. 2022

Preprint

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“…An enigmatic autoantibody, anti-Ro52/tripartite motif-containing protein 21 (TRIM21) IgG targets an intracellular 52 kDa protein involved in the anti-viral response by regulating interferon responses and acting as a cytoplasmic Fc receptor [1]. The autoantibody is not disease-specific and may be found in a range of systemic autoimmune diseases (SADs) such as Sjögren's syndrome (SS) and organ-specific autoimmune disorders, such as primary biliary cirrhosis (PBC) [2].…”

Section: Introductionmentioning

confidence: 99%

Anti-Ro52/TRIM21 serological subsets identify differential clinical and laboratory parameters

2022

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Introduction Anti-Ro52/tripartite motif-containing protein 21 (TRIM21) IgG is one of the most common autoantibodies found in systemic autoimmune diseases and is typically found in conjunction with anti-Ro60 and/or anti-La. A retrospective, cross-sectional study was undertaken to examine the clinical and laboratory features of two serological subsets: patients with anti-Ro52/TRIM21 autoantibodies in the absence of anti-Ro60 and anti-La (isolated anti-Ro52/TRIM21) and patients with anti-Ro52/TRIM21 in the presence of anti-Ro60 and/or anti-La. Methods Over a 12-month period, patients tested positive for anti-Ro52/TRIM21 via line immunoassay (LIA) at the Westmead Hospital (Australia) immunopathology laboratory were included. The presence of anti-Ro60 and/or anti-La via same LIA was noted. Associated laboratory and medical records were perused to extract demographic, laboratory, and clinical information. Results There were 346 patients within the study period, and 39.9% of the patients positive for anti-Ro52/TRIM21 lacked anti-Ro60/anti-La autoantibodies. Isolated anti-Ro52/TRIM21 patients tend to be older, have lower anti-Ro52/TRIM21 titres, have lower rheumatoid factors, and have lower proportions of neutropaenia compared to patients who were positive for anti-Ro52/TRIM21 and anti-Ro60/La. This occurred independent to diagnoses of Sjögren’s syndrome or systemic lupus erythematosus. Coexisting neurological syndromes, pulmonary pathologies, and malignancies were more prevalent in the isolated anti-Ro52/TRIM21 subset. Conclusions Patients with isolated anti-Ro52/TRIM21 tend to have distinct and important clinical and laboratory associations. It is unclear if these patients evolve or remain a stable subset and how they originate immunologically. Longitudinal and prospective studies are required to ascertain the overall predictive and prognostic value of this stratification. Key Points• Anti-Ro52/TRIM21 is an autoantibody found in autoimmunity and non-immunological conditions.• Sixty percent of anti-Ro52/TRIM21 patients are positive for anti-Ro60.• Isolated anti-Ro52/TRIM21 has reduced anti-Ro52/TRIM21 and rheumatoid factor titres.• Isolated anti-Ro52/TRIM21 is associated with anaemia and malignancies.

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“…The immune system is a defense network of cellular interactions covering the whole body, which recognizes non-self from self to repel attacking pathogens. 1 In the system, immune homeostasis builds the foundation of well-organized immune events. When the complex homeostasis is impaired, the host will react to autoantigen and trigger inflammation in tissues.…”

Section: Introductionmentioning

confidence: 99%

PD-1 Targeted Nanoparticles Inhibit Activated T Cells and Alleviate Autoimmunity via Suppression of Cellular Energy Metabolism Mediated by PKM2

Liu¹,

Xu²,

Li³

et al. 2022

IJN

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Background Effector T cells, especially T helper 1 (Th1) cells and T helper 17 (Th17) cells, are involved in the pathogenesis of many autoimmune diseases such as uveitis. Under hyperactive immune conditions, these effector T cells pathologically maintain a high expression level of programmed cell death protein 1 (PD-1) receptors and distinctively engage aerobic glycolysis via cellular energy metabolism mediated by pyruvate kinase M2 (PKM2). Therefore, we proposed that the synergy of metabolic inhibition and receptor guidance might target and down-regulate these hyperactive effector T cells to achieve anti-immune effects. Methods PD-1 antibody and TEPP-46 were integrated by polyethylene glycol (PEG) modified poly (lactic-co-glycolic acid) (PLGA) as a nanoplatform (TPP). Characteristics of TPP were basically detected. The biosafety of TPP was evaluated in vitro and in vivo. The targeting effect of TPP was detected by laser scanning confocal microscopy and flow cytometry (FCM). Interleukin-2 (IL-2)/interleukin-17A (IL-17A)/interferon-gamma (IFN-γ) producing cells were detected by FCM. Experimental autoimmune uveoretinitis (EAU) was induced in C57BL/6J mice as the inflammatory model. Results TPP had homogeneous distribution, good stability in vitro, and high biosafety in vitro and in vivo. Encapsulated TEPP-46 showed a sustained release profile with burst, steady and slow release periods. Early activation and proliferation of effector T cells was inhibited by TPP treatment in vitro. Th1 and Th17 cells were suppressed by TPP in vitro and in vivo. EAU was alleviated in mice by systemic administration of TPP. Conclusion The novel nanoplatform TPP could suppress Th1 and Th17 cells and exhibited an anti-inflammatory effect on EAU, providing an alternative approach to ameliorate autoimmune diseases mediated by these cells.

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TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease

Cited by 51 publications

References 187 publications

Regulation of protein translation by TRIM21

Regulation of protein translation by TRIM21

Anti-Ro52/TRIM21 serological subsets identify differential clinical and laboratory parameters

PD-1 Targeted Nanoparticles Inhibit Activated T Cells and Alleviate Autoimmunity via Suppression of Cellular Energy Metabolism Mediated by PKM2

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