ZFIN ID: ZDB-PUB-210526-9
In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR
Charbord, J., Ren, L., Sharma, R.B., Johansson, A., Ågren, R., Chu, L., Tworus, D., Schulz, N., Charbord, P., Stewart, A.F., Wang, P., Alonso, L.C., Andersson, O.
Date: 2021
Source: Nature metabolism   3: 682-700 (Journal)
Registered Authors: Charbord, Jeremie, Schulz, Nadja, Tworus, Dominika
Keywords: none
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
PubMed: 34031592 Full text @ Nat Metab
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.