GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development

  • Dev Cell. 2024 Jul 3:S1534-5807(24)00385-X. doi: 10.1016/j.devcel.2024.06.007.
Fan Zhao  1 ,  Zejin Cui  2 ,  Pengfei Wang  3 ,  Zhishan Zhao  2 ,  Kaixiang Zhu  4 ,  Yadan Bai  3 ,  Xuexiao Jin  1 ,  Lie Wang  5 ,  Linrong Lu  6
Affiliations
  • 1. Institute of Immunology and Department of Rheumatology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 2. Institute of Immunology and Department of Rheumatology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 3. Institute of Immunology and Department of Rheumatology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314100, China.
  • 4. Department of Cardiology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 5. Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314100, China; Bone Marrow Transplantation Center and Institute of Immunology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 6. Institute of Immunology and Department of Rheumatology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing 314100, China. Electronic address: [email protected].
PMID: 38981469 DOI: 10.1016/j.devcel.2024.06.007
Abstract

Mitochondria and endoplasmic reticulum contacts (MERCs) control multiple cellular processes, including cell survival and differentiation. Based on the observations that MERCs were specifically enriched in the CD4-CD8- double-negative (DN) stage, we studied their role in early mouse thymocyte development. We found that T cell-specific knockout of Hspa9, which encodes GRP75, a protein that mediates MERC formation by assembling the IP3R-GRP75-VDAC complex, impaired DN3 thymocyte viability and resulted in thymocyte developmental arrest at the DN3-DN4 transition. Mechanistically, GRP75 deficiency induced mitochondrial stress, releasing mitochondrial DNA (mtDNA) into the cytosol and triggering the type I interferon (IFN-I) response. The IFN-I pathway contributed to both the impairment of cell survival and DN3-DN4 transition blockage, while increased lipid peroxidation (LPO) played a major role downstream of IFN-I. Thus, our study identifies the essential role of GRP75-dependent MERCs in early thymocyte development and the governing facts of cell survival and differentiation in the DN stage.

Keywords
GRP75; IFN-I; cell survival; mitochondria-ER contacts; thymocyte development.
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