生物
胸腺细胞
细胞生物学
线粒体
细胞存活
细胞
癌症研究
细胞凋亡
免疫学
T细胞
生物化学
免疫系统
作者
Fan Zhao,NULL AUTHOR_ID,Pengfei Wang,NULL AUTHOR_ID,Kaixiang Zhu,NULL AUTHOR_ID,NULL AUTHOR_ID,NULL AUTHOR_ID,Linrong Lu
标识
DOI:10.1016/j.devcel.2024.06.007
摘要
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.
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