Identification of TBC1D30 interactors in murine MIN6 insulinoma cells.

ABSTRACT: Components of the insulin processing and secretion pathways remain incompletely understood. Here we examined a genome-wide association study (GWAS) locus associated with plasma proinsulin levels. Low-frequency GWAS variant rs150781447 encodes an Arg279Cys substitution in TBC1D30, but no role for this protein in insulin processing or secretion has been previously established. Using CRISPR/Cas9 genome editing in INS1 832/13 insulinoma cells, we generated clonal cell lines with altered TBC1D30. Compared to mock-edited cells, cell lines with reduced TBC1D30 expression or function showed significantly more secreted proinsulin, and to a lesser extent, secreted insulin. Cell lines with a partial deletion of a key functional domain showed increased expression of TBC1D30 and less secreted proinsulin. The effects on secretion corresponded to effects on intracellular proinsulin and insulin content. The interactome of TBC1D30, identified through affinity purification-mass spectrometry, was enriched in proteins involved in insulin trafficking and secretion. These findings suggest that the effects of rs150781447 on TBC1D30 are responsible for this GWAS signal and that TBC1D30 plays a critical role in the secretion of mature insulin.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

SUBMITTER: Christine Mills  

LAB HEAD: Karen Mohlke

PROVIDER: PXD047652 | Pride | 2026-06-08

REPOSITORIES: Pride