BIR‐2 is a Critical Component of Innate Immunity in C. elegans

Abstract

The eight-member BIR family of apoptosis inhibitors (IAPs) are critical mediators of immunity, cell cycle and apoptosis, and thus carcinogenesis. One, NAIP, acts as a component of both the inflammasome and cytokinetic machinery; and prevention of pathogenic oral-route bacteria from crossing the intestinal mucosa. At the same time, the isoforms of NAIP have been reported to also affect neuronal development, cytokinesis, inhibition of apoptosis and carcinogenesis. It is not clear whether NAIP is multifunctional or if these functions are interrelated, however there is great interest in using NAIP therapeutically to modulate innate immunity and cancer progression. To examine the NAIP function, we are taking advantage of the model organism C. elegans, a powerful experimental system for functional genomics and innate immunity, due to a well-characterized genome, rapid generation, ease of husbandry and RNA interference (RNAi). Furthermore, there are only two BIR family members, not eight: BIR-1 and BIR-2 with no known isoforms. BIR-1 has been demonstrated to be important for progression of cytokinesis but the role of BIR-2 is largely unknown. Our goal is to determine the physiological role of BIR-2, its relationship to BIR-1 and to the human BIR family, using C. elegans as a model system for innate immunity and apoptosis. The BIR-2 knockdown under standard conditions has minimal observable phenotype. However, we have demonstrated that survival of C. elegans in the face of an immune challenge is impaired when bir-2 was knocked down. LPS stimulation recapitulates the phenotype and mutant nematode strains illuminate the overlap with apoptosis pathways. RNAseq has revealed several networks of genes affected when bir-2 is knocked down, including the innate immune system and cuticle regulation. Based on the domain structure, expression patterns and effect on the immune system, our working hypothesis is that BIR-2 is a homolog of the human neuronal apoptosis inhibitory protein (NAIP).