细胞生物学
斑马鱼
细胞生长
细胞
细胞周期
ATF6
效应器
未折叠蛋白反应
化学
转录因子
生物
内质网
生物化学
基因
作者
Jérémie Charbord,Liang Ren,Rohit Sharma,Ada Johansson,Rasmus Ågren,Lianhe Chu,Dominika Tworus,Nadja Schulz,Pierre Charbord,Andrew F. Stewart,Peng Wang,Laura Alonso,Olov Andersson
标识
DOI:10.1038/s42255-021-00391-x
摘要
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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