TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus
The cGAS-STING signaling pathway serves as a pivotal surveillance mechanism for cytosolic double-stranded DNA (dsDNA) detection in mammalian systems. While STING-mediated type I interferon production is crucial for host defense, sustained activation of this pathway contributes to autoimmune patholog...
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| Format: | Article |
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China Science Publishing & Media Ltd.
2025-03-01
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| Series: | Acta Biochimica et Biophysica Sinica |
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| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2025046 |
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| author | Li Chen Ma Ang Bai Yu Liu Zitao Tian Linghan Wang Ziyuan Ma Huaishun Chen Zhengpu Gao Zhengheng Feng Shijie Fu Ping |
| author_facet | Li Chen Ma Ang Bai Yu Liu Zitao Tian Linghan Wang Ziyuan Ma Huaishun Chen Zhengpu Gao Zhengheng Feng Shijie Fu Ping |
| author_sort | Li Chen |
| collection | DOAJ |
| description | The cGAS-STING signaling pathway serves as a pivotal surveillance mechanism for cytosolic double-stranded DNA (dsDNA) detection in mammalian systems. While STING-mediated type I interferon production is crucial for host defense, sustained activation of this pathway contributes to autoimmune pathologies, including systemic lupus erythematosus (SLE). Maintaining immune homeostasis requires precise regulation of STING activity to prevent hyperactivation. Our study identifies TRIM21 as a novel positive regulator of cGAS-STING signaling in SLE pathogenesis. Our results demonstrate that TRIM21 overexpression stabilizes STING by suppressing autophagic degradation, whereas TRIM21 depletion accelerates this clearance process. Mechanistically, TRIM21 catalyzes the K63-linked polyubiquitylation of the selective autophagy receptor p62/SQSTM1, disrupting its interaction with STING. This post-translational modification prevents the sequestration of STING into autophagosomes, thereby stabilizing the adaptor protein and amplifying downstream type I interferon responses. Our findings reveal a previously unrecognized regulatory circuit in which TRIM21 orchestrates cross-talk between ubiquitin signaling and autophagy to control STING turnover. The TRIM21-p62 axis represents a potential therapeutic target for attenuating pathological interferon production in STING-dependent autoimmune disorders. This work advances our understanding of immune regulation by demonstrating how E3 ligase-mediated ubiquitin modifications modulate cargo recognition in selective autophagy pathways. The identified mechanism provides new insights into the molecular interplay between protein ubiquitylation and autophagic degradation in maintaining the innate immune balance, offering novel perspectives for developing targeted therapies against interferonopathies associated with cGAS-STING hyperactivity. |
| format | Article |
| id | doaj-art-38c6bd4d695842a2a3a30d90c9d4eaa2 |
| institution | DOAJ |
| issn | 1672-9145 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | China Science Publishing & Media Ltd. |
| record_format | Article |
| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj-art-38c6bd4d695842a2a3a30d90c9d4eaa22025-08-20T03:05:43ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452025-03-015783484610.3724/abbs.202504620d259ccTRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosusLi Chen0Ma Ang1Bai Yu2Liu Zitao3Tian Linghan4Wang Ziyuan5Ma Huaishun6Chen Zhengpu7Gao Zhengheng8Feng Shijie9Fu Ping10["Department of Rheumatology and Clinical Immunology, the Second Affiliated Hospital of Kunming Medical University, Kunming 650032, China","Department of Scientific Research, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650118, China"]["Department of Rheumatology and Clinical Immunology, the Second Affiliated Hospital of Kunming Medical University, Kunming 650032, China"]["Department of Urology, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650118, China"]["Department of Scientific Research, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650118, China"]["Department of Scientific Research, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650118, China"]["Cancer Institute, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital, Kunming 650118, China"]["Department of Scientific Research, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650118, China"]["Department of Scientific Research, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650118, China"]["Department of Health Management and Tumor Screening Center, Yunnan Cancer Hospital, the Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming 650118, China"]["Department of Rheumatology and Clinical Immunology, the Second Affiliated Hospital of Kunming Medical University, Kunming 650032, China"]["Department of Rheumatology and Clinical Immunology, the Second Affiliated Hospital of Kunming Medical University, Kunming 650032, China"]The cGAS-STING signaling pathway serves as a pivotal surveillance mechanism for cytosolic double-stranded DNA (dsDNA) detection in mammalian systems. While STING-mediated type I interferon production is crucial for host defense, sustained activation of this pathway contributes to autoimmune pathologies, including systemic lupus erythematosus (SLE). Maintaining immune homeostasis requires precise regulation of STING activity to prevent hyperactivation. Our study identifies TRIM21 as a novel positive regulator of cGAS-STING signaling in SLE pathogenesis. Our results demonstrate that TRIM21 overexpression stabilizes STING by suppressing autophagic degradation, whereas TRIM21 depletion accelerates this clearance process. Mechanistically, TRIM21 catalyzes the K63-linked polyubiquitylation of the selective autophagy receptor p62/SQSTM1, disrupting its interaction with STING. This post-translational modification prevents the sequestration of STING into autophagosomes, thereby stabilizing the adaptor protein and amplifying downstream type I interferon responses. Our findings reveal a previously unrecognized regulatory circuit in which TRIM21 orchestrates cross-talk between ubiquitin signaling and autophagy to control STING turnover. The TRIM21-p62 axis represents a potential therapeutic target for attenuating pathological interferon production in STING-dependent autoimmune disorders. This work advances our understanding of immune regulation by demonstrating how E3 ligase-mediated ubiquitin modifications modulate cargo recognition in selective autophagy pathways. The identified mechanism provides new insights into the molecular interplay between protein ubiquitylation and autophagic degradation in maintaining the innate immune balance, offering novel perspectives for developing targeted therapies against interferonopathies associated with cGAS-STING hyperactivity.https://www.sciengine.com/doi/10.3724/abbs.2025046systemic lupus erythematosuscGAS-STING signalingautophagyubiquitylationTRIM21p62/SQSTM1 |
| spellingShingle | Li Chen Ma Ang Bai Yu Liu Zitao Tian Linghan Wang Ziyuan Ma Huaishun Chen Zhengpu Gao Zhengheng Feng Shijie Fu Ping TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus Acta Biochimica et Biophysica Sinica systemic lupus erythematosus cGAS-STING signaling autophagy ubiquitylation TRIM21 p62/SQSTM1 |
| title | TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus |
| title_full | TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus |
| title_fullStr | TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus |
| title_full_unstemmed | TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus |
| title_short | TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus |
| title_sort | trim21 promotes type i interferon by inhibiting the autophagic degradation of sting via p62 sqstm1 ubiquitination in systemic lupus erythematosus |
| topic | systemic lupus erythematosus cGAS-STING signaling autophagy ubiquitylation TRIM21 p62/SQSTM1 |
| url | https://www.sciengine.com/doi/10.3724/abbs.2025046 |
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