GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development.
Dev Cell
; 59(19): 2643-2658.e7, 2024 Oct 07.
Article
em En
| MEDLINE
| ID: mdl-38981469
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.
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Base de dados:
MEDLINE
Assunto principal:
Diferenciação Celular
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Sobrevivência Celular
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Proteínas de Choque Térmico HSP70
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Retículo Endoplasmático
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Timócitos
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Mitocôndrias
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article