TBK1 regulates regeneration of pancreatic β-cells

• Published in: Scientific reports 2020-11, Vol.10 (1), p.19374-19374, Article 19374
• Main Authors: Jia, Yun-Fang, Jeeva, Subbiah, Xu, Jin, Heppelmann, Carrie Jo, Jang, Jin Sung, Slama, Michael Q., Tapadar, Subhasish, Oyelere, Adegboyega K., Kang, Sang-Moo, Matveyenko, Aleksey V., Peterson, Quinn P., Shin, Chong Hyun
• Format: Article
• Language: English
• Subjects: 631/80; 631/92; Acrylic acid; Animals; Beta cells; Cell cycle; Cell differentiation; Cell Line, Tumor; Cell Proliferation; Cyclic AMP; Diabetes; Diabetes mellitus; Gene expression; Gene Expression Regulation, Enzymologic; Gene Silencing; Genetic analysis; Human Embryonic Stem Cells - enzymology; Humanities and Social Sciences; Humans; Insulin; Insulin - genetics; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - enzymology; Kinases; multidisciplinary; Pancreas; Phosphodiesterase; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - genetics; Proteomics; Rats; Regeneration; Science; Science (multidisciplinary); Stem cells; Streptozocin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-76600-6

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of ( E )3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells.