TMED4 facilitates regulatory T cell suppressive function via ROS homeostasis in tumor and autoimmune mouse models
Endoplasmic reticulum stress (ERS) plays crucial roles in maintaining Treg stability and function, yet the underlying mechanism remains largely unexplored. Here, we demonstrate that (Tmed4ΔTreg) mice with Treg-specific KO of ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) had more Tregs with impaired Foxp3 stability, Treg signatures, and suppressive activity, which led to T cell hyperactivation and an exacerbated inflammatory phenotype and boosted antitumor immunity in mice. Mechanistically, loss of Tmed4 caused defects in ERS and a nuclear factor erythroid 2-related factor 2-related (NRF2-related) antioxidant response, which resulted in excessive ROS that reduced the Foxp3 stability and suppressive function of Tregs in an IRE1α/XBP1 axis-dependent manner. The abnormalities could be effectively rescued by the ROS scavenger, NRF2 inducer, or by forcible expression of IRE1α. Moreover, TMED4 suppressed IRE1α proteosome degradation via the ER-associated degradation (ERAD) system including the ER chaperone binding immunoglobulin protein (BIP). Our study reveals that TMED4 maintained the stability of Tregs and their suppressive function through IRE1α-dependent ROS and the NRF2-related antioxidant response.
Authors
- Zhenyan Jiang (ORCID: https://orcid.org/0000-0003-4594-7065)
- E Wu (ORCID: https://orcid.org/0000-0003-4587-6420)
- Hongrui Xiang
- Yuexiao Tao (ORCID: https://orcid.org/0000-0003-3820-0553)
- Yong Liu (ORCID: https://orcid.org/0000-0001-7395-4153)
- Bing Su (ORCID: https://orcid.org/0000-0003-0871-7666)
- Zhengting Wang (ORCID: https://orcid.org/0000-0001-5533-5711)
- Huizi Wang (ORCID: https://orcid.org/0000-0002-3652-6210)
- Chenyang Guan (ORCID: https://orcid.org/0009-0008-6422-7729)
- Youjin Hao
- Hongrui Duo (ORCID: https://orcid.org/0000-0001-8683-015X)
- Xuefeng Wu (ORCID: https://orcid.org/0000-0002-6933-7280)
- Kun Zhang (ORCID: https://orcid.org/0000-0002-8916-556X)
- Xin Li (ORCID: https://orcid.org/0000-0003-2525-9679)
- Lee Jia (ORCID: https://orcid.org/0000-0001-6839-5545)
- Jiamin Liu (ORCID: https://orcid.org/0009-0007-9802-5562)
- Zhaoyuan Hou (ORCID: https://orcid.org/0000-0003-0634-2020)
- Bin Li (ORCID: https://orcid.org/0000-0001-9861-3961)
- Jun Ni (ORCID: https://orcid.org/0009-0002-6105-9455)
- Peng Zhang (ORCID: https://orcid.org/0009-0004-7146-1805)
- Bo Li (ORCID: https://orcid.org/0009-0001-2833-2125)
- Xiaoxia Wang (ORCID: https://orcid.org/0000-0002-3165-6227)
- Xinyu Wang (ORCID: https://orcid.org/0009-0001-3927-0548)
Institutions
- Shanghai University (CN)
- Chongqing Normal University (CN)
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- Wuhan University (CN)
- Tongren Hospital (CN)
- Ministry of Education (TH)
- Songjiang District Central Hospital (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-10-31
- DOI
- https://doi.org/10.1172/jci179874
- Citations
- 19
- Primary Topic
- Complement system in diseases
- Type
- article
- Field-Weighted Citation Impact
- 4.57
Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- Shanghai Jiao Tong University
- School of Medicine, Shanghai Jiao Tong University
- National Key Research and Development Program of China
- National Key Research and Development Program of China Stem Cell and Translational Research
- Science and Technology Innovation Plan Of Shanghai Science and Technology Commission