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Effect of GRP75 deficiency on gene expression in DN3 thymocytes

ABSTRACT: Mitochondria and endoplasmic reticulum contacts (MERCs) regulate 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 thymocyte development. We found that T-cell-specific knockout of Hspa9, which encodes GRP75, a chaperone 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. 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 reveals the essential role of GRP75-dependent MERCs in early thymocyte development and uncovers the governing facts of cellular survival and differentiation in the DN stage.

ORGANISM(S): Mus musculus

PROVIDER: GSE268197 | GEO | 2024/06/08

REPOSITORIES: GEO

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