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

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GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development
Developmental Cell ( IF 10.7 ) Pub Date : 2024-07-08 , 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

Affiliation

Institute of Immunology and Department of Rheumatology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
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.
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.
Department of Cardiology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
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.
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.

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.

中文翻译：

GRP75 依赖性线粒体-ER 接触可确保小鼠胸腺细胞早期发育过程中的细胞存活

线粒体和内质网接触（MERC）控制多种细胞过程，包括细胞存活和分化。基于 MERCs 在 CD4-CD8-双阴性（DN）阶段特异性富集的观察结果，我们研究了它们在小鼠早期胸腺细胞发育中的作用。我们发现 H spa9 的 T 细胞特异性敲除，Hspa9 编码 GRP75，一种通过组装 IP3R-GRP75-VDAC 复合物介导 MERC 形成的蛋白质，损害了 DN3 胸腺细胞活力，并导致胸腺细胞发育停滞在 DN3-DN4 转换。从机制上讲，GRP75 缺陷诱导线粒体应激，将线粒体 DNA （mtDNA）释放到胞质溶胶中并触发 I 型干扰素（IFN-I）反应。IFN-I 通路导致细胞存活受损和 DN3-DN4 转换阻塞，而脂质过氧化（LPO）增加在 IFN-I 下游起主要作用。因此，我们的研究确定了 GRP75 依赖性 MERCs 在早期胸腺细胞发育中的重要作用以及 DN 阶段细胞存活和分化的支控事实。

更新日期：2024-07-08

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