Non-overlapping requirements of ASNA-1 function for insulin secretion, cisplatin resilience, and growth revealed by genetic analysis of point mutants in C. elegans

ABSTRACT ASNA1 plays an essential role in cisplatin chemotherapy response, type 2 diabetes, and heart disease. It is also an important biomarker in the treatment response of many diseases. Biochemically, ASNA1 has two mutually exclusive redox modulated roles: a tail-anchored protein (TAP) targeting function in the reduced state and a holdase/chaperone function in the oxidized state. Assigning biochemical roles of ASNA-1 to biomedical functions is crucial for successful therapy development. Our previous work showed the relevance of the C. elegans ASNA-1 homolog in modeling cisplatin response and insulin secretion. Here we analyzed two-point mutants in highly conserved residues in C. elegans ASNA-1 and identified their importance in separating cisplatin response from its roles in insulin secretion. Further, using targeted depletion we showed asna-1 tissue requirements for C. elegans growth and development. We concluded that, targeting single residues in ASNA-1 affecting Switch I/II domain function, in comparison to complete knockdown counteracted cisplatin resistance without jeopardizing other important biological functions. Taken together, our study shows that effects on health caused by ASNA1 mutations can have different biochemical bases.