期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 100, 期 18, 页码 10382-10387出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1832170100
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资金
- NIDDK NIH HHS [DK60837-01A1, DK36024, DK32520, R01 DK025306, R01 DK049106, R01 DK060837, DK25306, P30 DK032520, DK49106] Funding Source: Medline
Apoptosis is a regulated cell death program controlled by extrinsic and intrinsic signaling pathways. The intrinsic pathway involves stress signals that activate pro-apoptotic members of the Bcl-2 family, inducing permeabilization of mitochondria and release of apoptogenic factors. These proteins localize to the outer mitochondrial membrane. lan4, a mitochondrial outer membrane protein with GTP-bincling activity, is normally present in thymocytes, T cells, and B cells. We and others have recently discovered that a mutation in the rat lan4 gene results in severe T cell lymphopenia that is associated with the expression of autoimmune diabetes. The mechanism by which lan4 controls T cell homeostasis is unknown. Here we show that the absence of lan4 in T cells causes mitochondrial dysfunction, increased mitochondrial levels of stress-inducible chaperonins and a leucine-rich protein, and T cell-specific spontaneous apoptosis. T cell activation and caspase 8 inhibition both prevented apoptosis, whereas transfection of T cells with lan4-specific small interfering RNA recapitulated the apoptotic phenotype. The findings establish lan4 as a tissue-specific regulator of mitochondrial integrity.
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