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

Jérémie Charbord, Lipeng Ren, Rohit B. Sharma, Anna Johansson, Rasmus Ågren, Lianhe Chu, Dominika Tworus, Nadja Schulz, Pierre Charbord, Andrew F. Stewart, Peng Wang, Laura C. Alonso, Olov Andersson

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish
Pages (from-to)682-700
Number of pages19
JournalNature Metabolism
Volume3
Issue number5
DOIs
StatePublished - May 2021

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