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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\u2019s 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\u2013derived macrophages. Although Trim21 expression was induced in an IFN-I\u2013dependent 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\u2013induced 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\u2013related factor 2 (NRF2)\u2013dependent antioxidative genes. Collectively, our results identify IFN-I\u2013inducible 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.<\/jats:p>","DOI":"10.4049\/jimmunol.2000048","type":"journal-article","created":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T20:21:32Z","timestamp":1600460492000},"page":"2456-2467","source":"Crossref","is-referenced-by-count":29,"title":["TRIM21 Is Targeted for Chaperone-Mediated Autophagy during <i>Salmonella<\/i> Typhimurium Infection"],"prefix":"10.1093","volume":"205","author":[{"given":"Nina Judith","family":"Hos","sequence":"first","affiliation":[{"name":"Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine, University Hospital Cologne, University of Cologne , 50935 Cologne ,","place":["Germany"]},{"name":"Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases, University of Cologne , 50931 Cologne ,","place":["Germany"]},{"name":"German Center for Infection Research, Partner Site Bonn-Cologne , 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Ageing , 50931 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5408-0478","authenticated-orcid":false,"given":"Raja","family":"Ganesan","sequence":"additional","affiliation":[{"name":"Center for Cancer Biology, SA Pathology, University of South Australia , Adelaide, South Australia 5001 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9767-1999","authenticated-orcid":false,"given":"Ambika M V","family":"Murthy","sequence":"additional","affiliation":[{"name":"Center for Cancer Biology, SA Pathology, University of South Australia , Adelaide, South Australia 5001 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Rybniker","sequence":"additional","affiliation":[{"name":"German Center for Infection Research, Partner Site Bonn-Cologne , 50931 Cologne ,","place":["Germany"]},{"name":"Division of Infectious Diseases, Department I of Internal Medicine, University of Cologne , 50937 Cologne ,","place":["Germany"]},{"name":"Center for Molecular Medicine Cologne, University of Cologne , 50931 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7126-9814","authenticated-orcid":false,"given":"Sharad","family":"Kumar","sequence":"additional","affiliation":[{"name":"Center for Cancer Biology, SA Pathology, University of South Australia , Adelaide, South Australia 5001 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kr\u00f6nke","sequence":"additional","affiliation":[{"name":"Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine, University Hospital Cologne, University of Cologne , 50935 Cologne ,","place":["Germany"]},{"name":"Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases, University of Cologne , 50931 Cologne ,","place":["Germany"]},{"name":"German Center for Infection Research, Partner Site Bonn-Cologne , 50931 Cologne ,","place":["Germany"]},{"name":"Center for Molecular Medicine Cologne, University of Cologne , 50931 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7361-9491","authenticated-orcid":false,"given":"Nirmal","family":"Robinson","sequence":"additional","affiliation":[{"name":"Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine, University Hospital Cologne, University of Cologne , 50935 Cologne ,","place":["Germany"]},{"name":"Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases, University of Cologne , 50931 Cologne ,","place":["Germany"]},{"name":"Center for Cancer Biology, SA Pathology, University of South Australia , Adelaide, South Australia 5001 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