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Genome-wide CRISPR screen identified a role for commander complex mediated ITGB1 recycling in basal insulin secretion


Yang LLiu , Fye MAMargret A , Yang BBingyuan , Tang ZZihan , Zhang YYue , Haigh SSander , Covington BABrittney A , Bracey KKai , Taraska JJustin , Kaverina IIrina , Qu SShen , Chen WWenbiao . Molecular metabolism. 2022 7 11; (). 101541


OBJECTIVES: Pancreatic beta cells secrete insulin postprandially and during fasting to maintain glucose homeostasis. Although glucose stimulated insulin secretion (GSIS) has been extensively studied, much less is known about basal insulin secretion. Here, we performed a genome-wide CRISPR/Cas9 knockout screen to identify novel regulators of insulin secretion.

METHODS: To identify genes that cell autonomously regulate insulin secretion, we engineered a Cas9-expressing MIN6 subclone that permits irreversible fluorescence labeling of exocytic insulin granules. Using a fluorescence-activated cell sorting assay of exocytosis in low glucose and high glucose conditions in individual cells, we performed a genome-wide CRISPR/Cas9 knockout screen.

RESULTS: We identified several members of the COMMD family, a conserved family of proteins with central roles in intracellular membrane trafficking, as positive regulators of basal insulin secretion, but not GSIS. Mechanistically, we show that the Commander complex promotes insulin granules docking in basal state. This is mediated, at least in part, by its function in ITGB1 recycling. Defective ITGB1 recycling reduces its membrane distribution, the number of focal adhesions and cortical ELKS-containing complexes.

CONCLUSIONS: We demonstrated a previously unknown function of the Commander complex in basal insulin secretion. We showed that by ITGB1 recycling, Commander complex increases cortical adhesions, which enhances the assembly of the ELKS-containing complexes. The resulting increase in the number of insulin granules near the palsma membrane strengthens basal insulin secretion.