Speaker: Fred W. Perrino, PhD
Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA

HOST

Dr. Antonio Celada, IRB Barcelona

ABSTRACT

The proper metabolism of DNA and RNA polynucleotides in humans is critical to prevent the inappropriate activation of the immune response. Failure to process polynucleotides in cells can lead to the detection of these misplaced macromolecules by nucleic acid sensors designed to recognize foreign DNA and RNA of virus and bacterial pathogens. The inappropriate detection of self-nucleic acid polynucleotides originating from diverse metabolic processes and the subsequent induction of type-I interferons activate the immune system resulting in a spectrum of autoimmune disease phenotypes in humans. The TREX1, RNase H2 complex, and SAMHD1 proteins appear to function in a common molecular pathway to prevent endogenous nucleic acid polynucleotides from accumulating to levels sufficient to induce an interferon-mediated immune response. Mutations in TREX1, the three RNase H2 genes and the SAMHD1 gene cause Aicardi-Goutieres syndrome (AGS). TREX1 mutations have been linked to a spectrum of clinically related autoimmune disorders including AGS, familial chilblain lupus, some cases of systemic lupus erythematosus, and to retinal vasculopathy and cerebral leukodystrophy. Our work attempts to understand how the specific mutations identified in families and in individuals with these related autoimmune diseases impact on the functional properties of these enzymes or on the molecular pathways in which these enzymes function. The long-term goal of our work is to understand how TREX1, RNase H2, and SAMHD1 process polynucleotide macromolecules and how dysfunctions of these enzymes cause the pathological findings associated with these autoimmune diseases.

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