Structural and Biochemical Examination of Aberrant dsDNA Metabolism in TREX1-associated Autoimmunity

TREX1 is a 3&rsquo; exonuclease that degrades both single&ndash; and double&ndash;stranded polynucleotides in order to facilitate orderly cell death and prevent immune dysfunction. Mutations in the TREX1 gene at positions Asp&ndash;18 and Asp&ndash;200 lead to dominant autoimmune phenotypes associated with familial chilblain lupus and Aicardi&ndash;Goutieres syndrome. The TREX1 dimer localizes to the perinuclear space and translocates to the nucleus to degrade genomic DNA during apoptosis. Accumulation of self&ndash;dsDNA antibodies accompanies dysfunctional TREX1 and triggers the innate immune response. TREX1&ndash;associated dominant disease phenotypes correlate to an inability of TREX1 heterodimers containing one dominant&ndash;mutant protomer to efficiently degrade dsDNA substrates coupled with their inhibition of TREX1<super>WT</super> activity on dsDNA. A competition assay was designed using TREX1 dominant mutants and variants to demonstrate that an intact DNA binding process, coupled with dysfunctional chemistry in the active sites, explains the dominant phenotypes in <italic>TREX1</italic> alleles. A follow&ndash;up assay reported that the presence of dsDNA also inhibits heterodimer and wild type activity on ssDNA and that the mutant protomer, when bound in an inactive complex, prevents activity in the opposing active protomer.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2013

Author dc:creator

• Fye, Jason

• Autoimmunity

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/39134

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/39134