Proinsulin dependent interaction between ENPL-1/GRP94 and ASNA-1 in neurons is required to maintain insulin secretion in C. elegans.

Podraza-Farhanieh, A.; Raj, D.; Kao, G.; Naredi, P.

doi:10.1101/2022.06.15.496240

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bioRxiv · 10.1101/2022.06.15.496240

Proinsulin dependent interaction between ENPL-1/GRP94 and ASNA-1 in neurons is required to maintain insulin secretion in C. elegans.

Podraza-Farhanieh, A.·Raj, D.·Kao, G.·Naredi, P.

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Abstract

Maturation of insulin is crucial for insulin secretion and function. ENPL-1/GRP94/HSP90B1 plays an important role in this process. ASNA-1/TRC40/GET3 and ENPL-1/GRP94 are conserved insulin secretion regulators in Caenorhabditis elegans and mammals and mouse mutants display type 2 diabetes. ENPL-1 and GRP94 bind proinsulin and regulate proinsulin levels in C. elegans and cultured cells. Here we found that ASNA-1 and ENPL-1 co-operated to regulate insulin secretion in worms via a physical interaction that required pro-DAF-28/insulin but occurred independently of the insulin binding site of ENPL-1. ASNA-1 acted in neurons to promote DAF-28/insulin secretion. The interaction occurred in insulin expressing neurons and was sensitive to changes in pro-DAF-28 levels. The chaperone form of ASNA-1 is likely bound to ENPL-1. Loss of asna-1 disrupted Golgi trafficking pathways. ASNA-1 localization was affected in enpl-1 mutants and ENPL-1 overexpression partially bypassed ASNA-1 requirement. Taken together, we find a functional interaction between ENPL-1 and ASNA-1 which is necessary to maintain proper insulin secretion in C. elegans and provides insights about how their loss might produce diabetes in mammals.

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Podraza-Farhanieh, A., Raj, D., Kao, G., Naredi, P.. 2022-06-15. Proinsulin dependent interaction between ENPL-1/GRP94 and ASNA-1 in neurons is required to maintain insulin secretion in C. elegans.. https://doi.org/10.1101/2022.06.15.496240

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