Heterogeneous expression patterns of the T2D-associated kinesin-4 KIF21A in pancreatic islet endocrine cells.

BACKGROUND

The β cells in the pancreatic endocrine islets preferentially secrete insulin in specific subdomains of the plasma membrane adjacent to the vasculature (i.e., hot spots). Impaired insulin secretion and β -cell dysfunction are central features of Type-2 Diabetes, yet the cytoskeletal machinery that supports directional secretion and secretory hot spots remains incompletely defined. KIF21A is a plus-end-directed kinesin-4 motor protein that anchors microtubule plus ends to the cell cortex. However, the role of KIF21A in pancreatic islet endocrine cells and potential link to type 2 diabetes (T2D) remain unexplored.

METHODS

KIF21A mRNA and protein levels were analyzed using bulk RNA-seq and single-cell RNA-seq data using proteomics databases. Kif21a protein distribution was assessed by immunofluorescence in isolated mouse islets using super-resolution microscopy. Likewise, immunostaining of insulin, glucagon, somatostatin, laminin, and detyrosinated tubulin is also performed.

RESULTS

We show that KIF21A is downregulated in T2D human islets at both the mRNA (RNA-seq) and protein (quantitative proteomics) levels. We also demonstrate cell-type-specific enrichment of Kif21a protein (δ > α > β) in intact islets, confirming the hierarchy suggested by single-cell transcriptomics. We also show that within each endocrine lineage, Kif21a protein shows pronounced cell-to-cell heterogeneity, consistent with endocrine sub-states and functional specialization. And most importantly, we show that implicating Kif21a is spatially enriched at the rosettes and laminin-rich interfaces at vasculature-oriented secretion sites (hot spots), where microtubule anchoring is expected to shape targeted granule delivery.

CONCLUSIONS

KIF21A is a T2D-associated gene with cell-type-specific and heterogeneous expression in islet endocrine cells. KIF21A may have a cortical microtubule-anchoring function and may contribute to the directed granule delivery to the vasculature for regulated hormone secretion.