The autoantigen TRIM21 assembles proinflammatory immune complexes after lytic cell death

IF 16.4 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2026-04-17 DOI:10.1126/sciimmunol.ads9680

Esther L. Jones Evans, Benjamin Demarco, Han Cai, Madelon M.E. de Jong, Sarah Hill, Marcus A. Widdess, Joannah R. Fergusson, Ryan E. Glass, Gemma Harris, Gracie J. Mead, Yavuz F. Yazicioglu, Saba Nayar, Benjamin A. Fisher, Mark S. Cragg, Alexander J. Clarke, Audrey Gérard, Jelena S. Bezbradica, Lynn B. Dustin

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引用次数: 0

Abstract

Sjögren’s disease (SjD) causes localized and systemic inflammation and autoantibody production against intracellular proteins such as TRIM21/Ro52 (tripartite motif-containing protein 21). TRIM21, an E3 ubiquitin ligase, binds antibody Fc domains on opsonized pathogens that have escaped extracellular immunity and entered the cytosol. TRIM21 then ubiquitinates these pathogens, driving their proteasomal degradation. How TRIM21 becomes an autoantigen remains unclear. We show that TRIM21 is released upon lytic cell death (pyroptosis or necroptosis) but not apoptosis. Although many cytosolic proteins are released by dead cells, liberated TRIM21 is distinct: Its high antibody affinity enables binding to Fc domains of circulating immunoglobulins, forming large immune complexes (ICs). These ICs increase in SjD, where anti-TRIM21 autoantibodies interact with released TRIM21 via Fc and F(ab′)₂. TRIM21 ICs are taken up by macrophages, which drive proinflammatory responses, antigen presentation, and metabolic changes in high interferon environments. Thus, TRIM21 may perpetuate inflammation and autoantigen presentation, resulting in high immunogenicity.

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自身抗原TRIM21在溶解细胞死亡后组装促炎免疫复合物

Sjögren 's disease （SjD）引起局部和全身炎症，并产生针对细胞内蛋白（如TRIM21/Ro52（三方基元蛋白21））的自身抗体。TRIM21是一种E3泛素连接酶，它将抗体Fc结构域结合在已经逃脱细胞外免疫并进入细胞质的调理病原体上。然后TRIM21使这些病原体泛素化，驱动它们的蛋白酶体降解。TRIM21如何成为自身抗原尚不清楚。我们发现TRIM21在溶解性细胞死亡（焦亡或坏死）时释放，而不是凋亡。尽管许多细胞质蛋白被死细胞释放，但被释放的TRIM21是独特的：它的高抗体亲和力能够与循环免疫球蛋白的Fc结构域结合，形成大的免疫复合物（ic）。这些ic在SjD中增加，其中抗TRIM21自身抗体通过Fc和F(ab ') 2与释放的TRIM21相互作用。TRIM21 ic被巨噬细胞摄取，在高干扰素环境中驱动促炎反应、抗原呈递和代谢变化。因此，TRIM21可能使炎症和自身抗原呈递永久化，导致高免疫原性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.