Key Points IFN-I–inducible TRIM21 is degraded via CMA. S. Typhimurium activates mTORC2/Akt to impair CMA resulting in TRIM21 accumulation. High levels of TRIM21 contribute to S. Typhimurium–induced macrophage death. Visual Abstract Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative bacterium that induces cell death of macrophages as a key virulence strategy. We have previously demonstrated that the induction of macrophage death is dependent on the host’s type I IFN (IFN-I) response. IFN-I signaling has been shown to induce tripartite motif (TRIM) 21, an E3 ubiquitin ligase with critical functions in autoimmune disease and antiviral immunity. However, the importance and regulation of TRIM21 during bacterial infection remains poorly understood. In this study, we investigated the role of TRIM21 upon S. Typhimurium infection of murine bone marrow–derived macrophages. Although Trim21 expression was induced in an IFN-I–dependent manner, we found that TRIM21 levels were mainly regulated posttranscriptionally. Following TLR4 activation, TRIM21 was transiently degraded via the lysosomal pathway by chaperone-mediated autophagy (CMA). However, S. Typhimurium–induced mTORC2 signaling led to phosphorylation of Akt at S473, which subsequently impaired TRIM21 degradation by attenuating CMA. Elevated TRIM21 levels promoted macrophage death associated with reduced transcription of NF erythroid 2–related factor 2 (NRF2)–dependent antioxidative genes. Collectively, our results identify IFN-I–inducible TRIM21 as a negative regulator of innate immune responses to S. Typhimurium and a previously unrecognized substrate of CMA. To our knowledge, this is the first study reporting that a member of the TRIM family is degraded by the lysosomal pathway.

中文翻译：

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TRIM21靶向鼠伤寒沙门氏菌感染期间伴侣介导的自噬

关键点 IFN-I 诱导型 TRIM21 通过 CMA 降解。S. Typhimurium 激活 mTORC2/Akt 以损害 CMA，导致 TRIM21 积累。高水平的 TRIM21 有助于鼠伤寒沙门氏菌诱导的巨噬细胞死亡。视觉摘要 肠道沙门氏菌血清型鼠伤寒沙门氏菌 (S. Typhimurium) 是一种革兰氏阴性细菌，可诱导巨噬细胞的细胞死亡作为关键毒力策略。我们之前已经证明巨噬细胞死亡的诱导取决于宿主的 I 型干扰素 (IFN-I) 反应。IFN-I 信号已被证明可诱导三联基序 (TRIM) 21，这是一种 E3 泛素连接酶，在自身免疫性疾病和抗病毒免疫中具有关键功能。然而，TRIM21 在细菌感染过程中的重要性和调节作用仍然知之甚少。在这项研究中，我们调查了 TRIM21 对 S. 鼠骨髓源性巨噬细胞的鼠伤寒感染。尽管 Trim21 表达以 IFN-I 依赖性方式诱导，但我们发现 TRIM21 水平主要受转录后调节。TLR4 激活后，TRIM21 被伴侣蛋白介导的自噬 (CMA) 通过溶酶体途径瞬时降解。然而，鼠伤寒沙门氏菌诱导的 mTORC2 信号导致 Akt 在 S473 处磷酸化，随后通过减弱 CMA 来削弱 TRIM21 的降解。升高的 TRIM21 水平促进了与 NF 红系 2 相关因子 2 (NRF2) 依赖性抗氧化基因转录减少相关的巨噬细胞死亡。总的来说，我们的结果将 IFN-I 诱导型 TRIM21 鉴定为对鼠伤寒沙门氏菌和以前未被识别的 CMA 底物的先天免疫反应的负调节剂。据我们所知，