GIMAP5 regulates mitochondrial integrity from a distinct subcellular compartment.

Spontaneous apoptosis of T lymphocytes results in marked lymphopenia in the Biobreeding diabetes-prone (BB-DP) rat leading to the development of autoimmune type 1 diabetes. The lymphopenia phenotype in these rats is linked to the lyp locus. The lyp allele harbors a frameshift mutation within the gene encoding 'GTPase of immunity-associated nucleotide binding protein 5' (GIMAP5). Mechanisms underlying the pro-survival function of GIMAP5 in T lymphocytes are unclear. Overexpression studies have shown that GIMAP5 localizes within mitochondria and the endoplasmic reticulum (ER). We have used an antiserum raised against GIMAP5 to define its localization in rat primary T lymphocytes. We present evidence that endogenous GIMAP5 is associated with a sedimentable subcellular fraction that is distinct from mitochondria and the ER. These data are further supported by confocal microscopy using a GIMAP5 construct with an intact C-terminal membrane anchor. Nonetheless, T cells isolated from GIMAP5(lyp/lyp) rats display rapid loss of mitochondrial membrane potential. Our findings suggest that GIMAP5 regulates T lymphocyte survival by mechanisms that operate upstream of mitochondria.