Ian4 is required for mitochondrial integrity and T cell survival.
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. Ian4, a mitochondrial outer membrane protein with GTP-binding activity, is normally present in thymocytes, T cells, and B cells. We and others have recently discovered that a mutation in the rat Ian4 gene results in severe T cell lymphopenia that is associated with the expression of autoimmune diabetes. The mechanism by which Ian4 controls T cell homeostasis is unknown. Here we show that the absence of Ian4 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 Ian4-specific small interfering RNA recapitulated the apoptotic phenotype. The findings establish Ian4 as a tissue-specific regulator of mitochondrial integrity.
Pandarpurkar
Malini
M
Department of Medicine and Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Suite 218, Worcester, MA 01605, USA.
Wilson-Fritch
Leanne
L
Corvera
Silvia
S
Markholst
Helle
H
Hornum
Lars
L
Greiner
Dale L
DL
Mordes
John P
JP
Rossini
Aldo A
AA
Bortell
Rita
R
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000502:physiology; D002470:Cell Survival; D053938:DNA Fragmentation; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011920:Rats, Inbred WF; D013601:T-Lymphocytes / Q000502:physiology*
C425002:Ian4 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D020169:Caspases; D019204:GTP-Binding Proteins