A novel mouse model of proteasome associated autoinflammatory syndromes

Abstract

Abstract Proteasome associated autoinflammatory syndromes (PRAAS) represent a rare class of early-onset autoinflammatory diseases, including chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome). CANDLE is an inherited autosomal recessive disease associated with recurrent fevers, skin lesions, lipodystrophy and other comorbidities. Point mutations in the proteasome subunit beta type-8 (psmb8) gene, which encodes the beta-5i (ß5i) catalytic subunit of the 20S immunoproteasome, have been linked to CANDLE. The immunoproteasome is induced in cells in response to interferon (IFN) signaling. In cells lacking functional immunoproteasomes, oxidant-damaged proteins aggregate and likely create a feed-forward loop resulting in greater cytokine-mediated stress. We have developed a novel mouse model via targeted mutation within the psmb8 gene, which harbors a specific point mutation (224C>T) present in CANDLE patients. Our data shows that this mutation leads to marked differences in the expression of the immunoproteasome subunit ß5i within these mice. Thus, this mouse model is likely to exhibit changes in the immunoproteasome consistent with human disease upon interferon signaling. As mice with the targeted mutation do not directly yield a CANDLE-like phenotype at rest, it suggests that induction of disease-associated morbidity requires additional drivers. To test this, we are investigating interferons as initiators of disease pathogenesis. Future research will entail subjecting these mice to viral infection in order to identify if such triggers can initiate PRAAS-like symptoms in CANDLE patients. These mice may prove to an essential tool in understanding such disorders.