1. Academic Validation
  2. GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development

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

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: lu_linrong@zju.edu.cn.
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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