Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50935 Cologne, Germany;
Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
J Immunol. 2020 Nov 1;205(9):2456-2467. doi: 10.4049/jimmunol.2000048. Epub 2020 Sep 18.
serovar Typhimurium ( 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 Typhimurium infection of murine bone marrow-derived macrophages. Although 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, 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 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.
鼠伤寒沙门氏菌（Typhimurium）是一种革兰氏阴性细菌，它通过诱导巨噬细胞死亡作为关键的毒力策略。我们之前已经证明，巨噬细胞死亡的诱导依赖于宿主的 I 型干扰素（IFN-I）反应。IFN-I 信号已被证明诱导三结构域（TRIM）21，这是一种在自身免疫性疾病和抗病毒免疫中具有关键功能的 E3 泛素连接酶。然而，TRIM21 在细菌感染中的重要性和调节仍知之甚少。在这项研究中，我们研究了 TRIM21 在鼠源骨髓来源的巨噬细胞感染鼠伤寒沙门氏菌时的作用。尽管 表达是 IFN-I 依赖性诱导的，但我们发现 TRIM21 水平主要受转录后调节。TLR4 激活后，TRIM21 通过伴侣介导的自噬（CMA）通过溶酶体途径短暂降解。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 来抑制 TRIM21 降解。TRIM21 水平升高促进了与 NF 红细胞 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，我们的结果确定 IFN-I 诱导的 TRIM21 是对鼠伤寒沙门氏菌先天免疫反应的负调节剂，也是 CMA 的一个以前未被识别的底物。据我们所知，这是第一项报道 TRIM 家族成员通过溶酶体途径降解的研究。
