Hrd1 protects regulatory T cells from ER stress-induced instability and dysfunction Yuanming Xu1, Johanna Melo-Cardenas1, Hongjian Jin2, Jessica Heinrichs Voss3, Isabella Gau1 Juncheng Wei1, Elena Montauti1, Yusi Zhang1, Beixue Gao1, James M. Mathew3,4, Zhaolin Sun5 and Deyu Fang1,5# 1Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL, 60611, USA; 2Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA; 3Department of Surgery, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL, 60611, USA; 4Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL, 60611, USA 5Department of Pharmacology School of Pharmacy, Dalian Medical University, 9 Lvshun South Rd, Dalian, 116044, China #Corresponding Author: email@example.com, Tel: 312-503-3021 T regulatory cells (Treg) differentiation, maintenance, and function are controlled by the transcription factor FoxP3, which can be destabilized under inflammatory or other pathological conditions. However, the microenvironmental factors that compromise Treg identity and the underlying mechanisms remain unclear. Here, we show that ER stress destabilizes both human and mouse Treg by suppressing FoxP3 expression, suggesting a critical role of the ER stress response in maintaining Treg properties. We found that genetic deletion of Hrd1, an E3 ligase critical in suppressing the ER stress response, leads to elevated expression of ER stress-responsive genes in Treg. Importantly, mice with Treg-specific ablation of Hrd1 displayed massive multi-organ lymphocyte infiltration, body weight loss, and the development of severe small intestine inflammation with aging. At the molecular level, the deletion of Hrd1 led to upregulation of the ER stress response, in particular, the activation of the ER stress sensor IRE1. Impaired FoxP3 expression caused by Hrd1 deletion was largely rescued by an IRE1 kinase inhibitor. Taken together, these findings indicate that Hrd1 is crucial for maintaining the expression and suppressive function ofTreg through suppression of the IRE1-mediated ER stress response. The study is significant because it will help to fill fundamental gaps in our knowledge of the role of Hrd1 in T regulatory cells, which will inform the design of future immunotherapies for cancer patients or immune dysregulated diseases. This work was supported by National Institutes of Health (NIH) R01 grants (AI079056, AI108634 and AR006634) to D.F.
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