TRIM21 induces selective autophagy of viruses and bacteria

TRIM21 is an exceptionally versatile ubiquitin ligase that can be directed by antibodies to target oligomeric protein scaffolds, viral capsids, and proteopathic aggregates for intracellular degradation. How the cell degrades these typically resistant substrates remains poorly understood. To address this, we used TRIM21 viral restriction to create a genome-wide phenotypic screen for antibody-dependent capsid degradation. We identify an antimicrobial selective macroautophagy pathway in mammalian cells, which we term "antibody-directed xenophagy." We show this mechanism restricts structurally diverse pathogens, including adenovirus and Salmonella. Using quantitative microscopy, we demonstrate that TRIM21 rapidly intercepts antibody-pathogen complexes, leading to ubiquitin ligase activation. Following this, selective autophagy adaptors are recruited and viral cargoes are delivered to lysosomes. This process reduces Salmonella pathology and bacterial tissue invasion in mice. We propose that TRIM21 evolved through competition with pathogens to induce autophagy of diverse and complex substrates, potentially explaining its versatility for targeted protein degradation.TRIM21是一种功能极其多样的泛素连接酶（ubiquitin ligase），可通过抗体介导，靶向寡聚蛋白支架、病毒衣壳以及致病蛋白聚集物，使其经胞内途径降解。目前学界对于细胞如何降解这类通常具有抗性的底物仍知之甚少。为解决这一科学问题，我们利用TRIM21的病毒限制性特性，构建了针对抗体依赖性衣壳降解的全基因组表型筛选体系。我们在哺乳动物细胞中发现了一条抗菌选择性巨自噬（macroautophagy）通路，并将其命名为"抗体定向异种吞噬（antibody-directed xenophagy）"。我们证实该通路可限制结构多样的病原体，涵盖腺病毒与沙门氏菌。借助定量显微成像技术，我们证明TRIM21能够快速捕获抗体-病原体复合物，进而触发泛素连接酶的激活。在此之后，选择性自噬接头蛋白被招募，病毒货物被运送至溶酶体中。该过程可减轻小鼠体内沙门氏菌的致病效应与细菌组织侵袭能力。我们提出，TRIM21是通过与病原体的竞争演化而来，其功能是诱导对多种复杂底物的自噬降解，这一机制或可解释其在靶向蛋白质降解方面的多功能性。