PUBLICATION

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

Authors
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.
ID
ZDB-PUB-210526-9
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
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Errata and Notes