2. Academic Validation
  3. In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR

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.
Jérémie Charbord 1,  Lipeng Ren  # 1,  Rohit B Sharma  # 2,  Anna Johansson 3,  Rasmus Ågren 4,  Lianhe Chu 1,  Dominika Tworus 1,  Nadja Schulz 1,  Pierre Charbord 5,  Andrew F Stewart 6,  Peng Wang 6,  Laura C Alonso 2,  Olov Andersson 7
Affiliations

Affiliations

  • 1 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
  • 2 Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, New York, NY, USA.
  • 3 Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • 4 Department of Biology and Biological Engineering, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Chalmers University of Technology, Göteborg, Sweden.
  • 5 Sorbonne Université, Institut de Biologie Paris-Seine, CNRS UMR 7622, Inserm, Paris, France.
  • 6 Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. [email protected].
  • # Contributed equally.
PMID: 34031592 DOI: 10.1038/s42255-021-00391-x
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.

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