In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR

Nat Metab. 2021 May;3(5):682-700. doi: 10.1038/s42255-021-00391-x. Epub 2021 May 20.

Abstract

It is known that β cell proliferation expands the β cell mass during development and under certain hyperglycemic conditions in the adult, a process that may be used for β cell regeneration in diabetes. Here, through a new high-throughput screen using a luminescence ubiquitination-based cell cycle indicator (LUCCI) in zebrafish, we identify HG-9-91-01 as a driver of proliferation and confirm this effect in mouse and human β cells. HG-9-91-01 is an inhibitor of salt-inducible kinases (SIKs), and overexpression of Sik1 specifically in β cells blocks the effect of HG-9-91-01 on β cell proliferation. Single-cell transcriptomic analyses of mouse β cells demonstrate that HG-9-91-01 induces a wave of activating transcription factor (ATF)6-dependent unfolded protein response (UPR) before cell cycle entry. Importantly, the UPR wave is not associated with an increase in insulin expression. Additional mechanistic studies indicate that HG-9-91-01 induces multiple signalling effectors downstream of SIK inhibition, including CRTC1, CRTC2, ATF6, IRE1 and mTOR, which integrate to collectively drive β cell proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Drug Evaluation, Preclinical / methods*
  • Endoribonucleases / metabolism
  • Gene Expression Profiling
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Single-Cell Analysis
  • Unfolded Protein Response / drug effects*
  • Zebrafish

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • Protein Kinase Inhibitors
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • SIK1 protein, human
  • Endoribonucleases