CaltechAUTHORS
  A Caltech Library Service

TBK1 regulates regeneration of pancreatic β-cells

Jia, Yun-Fang and Jeeva, Subbiah and Xu, Jin and Heppelmann, Carrie Jo and Jang, Jin Sung and Slama, Michael Q. and Tapadar, Subhasish and Oyelere, Adegboyega K. and Kang, Sang-Moo and Matveyenko, Aleksey V. and Peterson, Quinn P. and Shin, Chong Hyun (2020) TBK1 regulates regeneration of pancreatic β-cells. Scientific Reports, 10 . Art. No. 19374. ISSN 2045-2322. PMCID PMC7653919. https://resolver.caltech.edu/CaltechAUTHORS:20201110-085608476

[img] PDF - Published Version
Creative Commons Attribution.

5Mb
[img] PDF - Supplemental Material
Creative Commons Attribution.

15Mb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20201110-085608476

Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41598-020-76600-6DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653919PubMed CentralArticle
ORCID:
AuthorORCID
Jeeva, Subbiah0000-0002-7983-1215
Jang, Jin Sung0000-0001-7199-4418
Slama, Michael Q.0000-0002-0808-3547
Tapadar, Subhasish0000-0002-9010-5687
Kang, Sang-Moo0000-0001-6198-331X
Matveyenko, Aleksey V.0000-0001-7761-4842
Peterson, Quinn P.0000-0001-8701-0575
Shin, Chong Hyun0000-0002-6385-5992
Additional Information:© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Received 14 December 2019; Accepted 22 October 2020; Published 09 November 2020. We thank Doo-Sup Choi, Mi Hyeon Jang, Ki Hyun Yoo, and Kensei Komatsu for discussions/advice for experimental procedures, and Hyunjung Kim for experimental assistance. We acknowledge the Mayo Clinic Mouse Facility for mouse care and the Microscopy and Cell Analysis Core at Mayo Clinic for technical support. The authors acknowledge funding support from the National Institutes of Health (R56DK111630 to C. H. S.; R01DK098468 to A. V. M; R01AI093772 to S-. M. K.), the Cullen-Peck Fund (to A. K. O.), and the Center for Regenerative Medicine at Mayo Clinic (to Q. P. P.). Data availability: The RNA-seq datasets supporting the current study are being deposited in a public repository (GSE136670). Author Contributions: C.H.S. conceived and designed the experiments. Y.F.J., S.J., J.X., C.J.H., M.Q.S., and C.H.S. performed the experiments. S.T. and A.K.O. synthesized and provided reagents/materials. Y.F.J., S.J., J.X., C.J.H., J.S.J., M.Q.S., A.V.M., Q.P.P., and C.H.S. analyzed the data. S-.M.K., A.V.M., Q.P.P., and C.H.S. reviewed the manuscript. A.V.M., Q.P.P., and C.H.S. wrote the manuscript. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIHR56DK111630
NIHR01DK098468
NIHR01AI093772
Cullen-Peck FundUNSPECIFIED
Mayo ClinicUNSPECIFIED
Subject Keywords:Cell biology; Chemical biology
PubMed Central ID:PMC7653919
Record Number:CaltechAUTHORS:20201110-085608476
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201110-085608476
Official Citation:Jia, Y., Jeeva, S., Xu, J. et al. TBK1 regulates regeneration of pancreatic β-cells. Sci Rep 10, 19374 (2020). https://doi.org/10.1038/s41598-020-76600-6
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:106586
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Nov 2020 17:49
Last Modified:16 Nov 2020 17:12

Repository Staff Only: item control page