Wolfe, D.; Saha, J.; Mitchell, J.; McCalpin, S.; Gutknecht, M.; Brooks, C. L.; Rothstein, T.; Ramamoorthy, A.

Insulin can misfold and assemble into amyloid fibrils, a process linked not only to complications of insulin therapy but also to proteotoxic stress in pancreatic beta cells. Despite growing interest in the pathological consequences of insulin aggregation, prevention efforts are limited by an incomplete understanding of the endogenous mechanisms that counteract it. Here, we identify Fas apoptosis inhibitory molecule (FAIM) as an endogenous suppressor of insulin amyloid formation. FAIM reduces beta sheet formation and redirects insulin toward disordered, growth incompetent assemblies. Further, FAIM attenuates the cytotoxicity of insulin aggregates in vitro. We hypothesize that this effect arises from masking aggregation prone regions of insulin and show through structural modeling that FAIM interacts with both insulin chains. These findings extend the anti-aggregation function of FAIM to insulin and suggest a mechanism for endogenous suppression of insulin amyloid formation. More broadly, our results provide insight into the regulation of insulin assembly and highlight FAIM as a candidate modulator of proteostasis in metabolic disease.