Dominant TREX1 alleles in autoimmune disease

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

DESCRIPTION (provided by applicant): Mutations in TREX1, the most common exonuclease found in mammalian cells, has been linked to a number of auto-immune diseases such as Aicardi-Goutieres syndrome, Systemic Lupus Erythematosus, Familial Chilblain Lupus and to Retinal Vasculopathy and Cerebral Leukodystrophy. Heterozygous dominant TREX1 alleles that cause disease can be separated into two categories;active site point mutations (catalytically deficient) and frame shift mutations that truncate the C-terminal region (location deficient). The C-terminal region of TREX1 associates with the SET complex that is localized with the ER until recruitment to the nucleus upon cellular oxidative stress or activation of a cell death pathway. Accumulating data indicates a role for TREX1 in the degradation of cellular retroelements, cytosolic single-stranded DNA, and genomic DNA suggesting multiple nucleic acid metabolic pathways for TREX1 function. Structural data for dimeric TREX1 has provided insight into the activity of this enzyme on single-stranded and double-stranded DNA;however, much work remains to better understand the contribution of TREX1 mutations to the development of autoimmune disease. This research will elucidate the biochemical mechanism of TREX1 dominant catalytic and truncation mutations on various DNA substrates. These mutations will be introduced into mouse embryonic stem (ES) cells to measure the ability of the cells to proceed through an induced cell death pathway in which TREX1 plays a significant role. The degradation of genomic DNA will be quantified to determine the activity of TREX1 on this substrate. This work will provide information regarding the molecular structure of the TREX1 in vivo substrate its contribution to a sustained innate immune response. PUBLIC HEALTH RELEVANCE: The autoimmune diseases Aicardi-Goutieres syndrome, familial chilblain lupus, systemic lupus erythematosus, and retinal vasculopathy and cerebral leukodystrophy have been linked to mutations in TREX1, the most common exonuclease in mammalian cells. This work will provide information regarding the function of TREX1 in the cell by focusing on dominant alleles that have been identified in autoimmune patients. Additionally, this work will provide insight into the role of TREX1 in the development of autoimmune disorders.