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

ABSTRACT: Maturation of insulin is crucial for insulin secretion and function. ENPL[1]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]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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human) Caenorhabditis Elegans

TISSUE(S): Brain

SUBMITTER: Johannes Fuchs

LAB HEAD: Gautam Kao

PROVIDER: PXD038504 | Pride | 2023-03-10

REPOSITORIES: Pride

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			Action	DRS
	3048_UNIhuman_0miss_norm_ungrouped.msf	Msf
	3048_UNIhuman_0miss_norm_ungrouped.pdResult	Other
	3048_UNIhuman_0miss_norm_ungrouped_FDR1perc.xlsx	Xlsx
	Fusion_190211_21.raw	Raw
	Fusion_190211_22.raw	Raw

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