Function of RNase Inhibitor 1 in the pathogenesis of systemic autoimmunity

• Applicant: Dr. Barbara Kind
• Subject Area: Pediatric and Adolescent Medicine ; Human Genetics ; Immunology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 287870170

Function of RNase Inhibitor 1 in the pathogenesis of systemic autoimmunityHereditary defects in the metabolism of intracellular nucleic acids cause Typ I IFN response and may lead to systemic autoimmunity. The phenotype of mutations in the DNase TREX1, the RNase H2, the dNTPase SAMHD1, the RNA-editing enzyme ADAR1 and the cytosolic RNA sensor IFIH1 includes cutaneous and systemic forms of lupus erythematosus and the rare monogenic disorder Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy that clinically resembles in-utero-acquired viral infection. Nucleic acids are the major danger motifs originated from viruses or other pathogens and recognized by sensors of the innate immune system. Besides this, endogenous nucleic acids are also formed during physiological processes such as DNA replication and DNA repair. Degradation of this metabolic intermediates has to be tightly regulated to avoid activation of the innate immune system. An inadequate repair capacity of RNase H2 causes an accumulation of single ribonucleotides embedded in genomic DNA and induces a p53-dependent DNA damage response. RNase H2 removes ribonucleotides from DNA to maintain genome integrity. How RNase H2 malfunction causes systemic autoimmunity remains still an open question. The aim of this project is to identify molecular mechanisms, which are regulating RNase H2 function. In particular, this will be addressed on a currently identified regulator, the RNase inhibitor 1 (RNH1). The expected results will contribute to a better understanding of the regulation of RNase H2 and the pathogenesis of systemic autoimmunity.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Min Ae Lee-Kirsch