GSE136670
TBK1 Regulates Regeneration of Pancreatic b-cells
b-cell proliferation induction is one of the most tangible therapeutic strategies to restore b-cell mass. However, this approach has proven challenging due to a remarkable resistance of adult human b-cells to proliferation. Here we aim to unravel the role of a non-canonical IkB kinase TBK1 (TANK-binding kinase 1), which is predominantly expressed in b-cells in mammalian islets, in regulating cell cycle progression. Genetic silencing of TBK1 in INS-1 832/13 rat b-cell line promoted proliferation of b-cells. Proteomic and transcriptome analyses further revealed changes of proteins and genes critical for cell growth and proliferation, including upregulation of ribosomal proteins and cell cycle regulators, upon depletion of TBK1. TBK1 overexpression decreased sensitivity of b-cells to the elevation of cAMP levels and reduced proliferation of b-cells in a manner dependent on the activity of phosphodiesterase 3 (PDE3). Importantly, pharmacological inhibition of TBK1 using (E)3-(3-phenylbenzo[c]isoxazol-5-yl) acrylic acid (PIAA) augmented proliferation and function of rat and human embryonic stem cell (hESC)-derived insulin-producing b-cells under basal conditions. Diabetogenic insults further induced TBK1 expression and accordingly, PIAA protected b-cells against cytokine- and streptozotocin-induced diabetogenic challenges and promoted b-cell replication. Furthermore, PIAA increased proliferation of ß-cells in normal and type 2 diabetic human islets with elevation in insulin secretion. Altogether, these data unveil novel and essential function of TBK1 as a key cell-autonomous negative regulator of b-cell replication and presenting PIAA as a valid therapeutic strategy for augmenting proliferation and function of b-cells. Overall design: Transfected TBK1 siGENOME SMARTpool siRNA or negative control non-targeting siRNA into INS-1 832/13 beta-cells for 36 hours.