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

Charbord J, Ren L, Sharma RB, Johansson A, Ågren R, Chu L, Tworus D, Schulz N, Charbord P, Stewart AF, Wang P, Alonso LC, Andersson O

Nat Metab 3 (5) 682-700 [2021-05-00; online 2021-05-20]

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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PubMed 34031592

DOI 10.1038/s42255-021-00391-x

Crossref 10.1038/s42255-021-00391-x

pii: 10.1038/s42255-021-00391-x