|ZFIN ID: ZDB-PUB-210526-9|
In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR
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.
|Source:||Nature metabolism 3: 682-700 (Journal)|
|Registered Authors:||Charbord, Jeremie, Schulz, Nadja, Tworus, Dominika|
|PubMed:||34031592 Full text @ Nat Metab|
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.
ABSTRACTIt 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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