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
-
- Single-Cell Analysis
- Protein Kinase Inhibitors/pharmacology*
- Zebrafish
- Signal Transduction
- Drug Evaluation, Preclinical/methods*
- Gene Expression Profiling
- Insulin-Secreting Cells/drug effects*
- Insulin-Secreting Cells/metabolism*
- Protein Serine-Threonine Kinases/antagonists & inhibitors*
- Protein Serine-Threonine Kinases/metabolism
- Cell Proliferation/drug effects
- Male
- Humans
- Unfolded Protein Response/drug effects*
- High-Throughput Nucleotide Sequencing
- Mice
- Activating Transcription Factor 6/metabolism
- Endoribonucleases/metabolism
- Animals
- Cell Cycle/drug effects
- PubMed
- 34031592 Full text @ Nat Metab
Citation
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. (2021) In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR. Nature metabolism. 3:682-700.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping