KANK1 regulates the positioning of liprin-α1 and the spatial organization of insulin granule fusion in pancreatic β cells

TL;DR

This study identifies KANK1 as a key protein that helps position insulin granules for release in pancreatic beta cells.

Contribution

The paper reveals a novel molecular mechanism involving KANK1 in directing insulin granule fusion at the capillary interface.

Findings

KANK1 knockdown disrupts the localization of liprin-α1 and reduces glucose-induced insulin secretion.

KANK1 links focal adhesion protein talin to liprin-β1, anchoring liprin-α1 at the capillary interface.

Local activation of focal adhesions at the capillary interface is the primary cue for β-cell orientation.

Abstract

In β cells, insulin granule fusion is enriched at the capillary interface, which targets insulin secretion directly into the bloodstream. The cues and molecular mechanisms used to target granule fusion to this area remain unknown. The capillary interface is characterized by local activation of focal adhesions and an enrichment of presynaptic scaffold proteins, including liprin-α1, the latter suggesting that a presynaptic-like mechanism might control the targeting of insulin granules to this region. Here, we show that the focal adhesion-associated adaptor protein KANK1 is locally enriched at the β-cell capillary interface and its knockdown disrupts the subcellular localization of liprin-α1. Moreover, KANK1 knockdown reduced glucose-induced insulin secretion and led to the mistargeting of insulin granule fusion. We provide evidence that KANK1 is a component in a complex that links the focal adhesion protein talin to liprin-β1, which in-turn anchors liprin-α1 through binding at its C-terminus. We conclude that the local activation of focal adhesions at the capillary interface provides the primary cue to orient the β-cell. The subsequent enrichment of KANK1 provides the molecular link between focal adhesion localization and the positioning of liprin-α1. Liprin-α1 is a key presynaptic scaffold protein, and although the mechanisms are not known, its local enrichment is likely to drive targeted insulin granule fusion.

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