In vivo screen identifies a SIK inhibitor that induces beta cell proliferation through a transient UPR
Artikel i vetenskaplig tidskrift, 2021

It is known that beta cell proliferation expands the beta cell mass during development and under certain hyperglycemic conditions in the adult, a process that may be used for beta 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 beta cells. HG-9-91-01 is an inhibitor of salt-inducible kinases (SIKs), and overexpression of Sik1 specifically in beta cells blocks the effect of HG-9-91-01 on beta cell proliferation. Single-cell transcriptomic analyses of mouse beta 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 beta cell proliferation. A high-throughput chemical screen identifies the salt-inducible kinase inhibitor HG-9-91-01 as a driver of beta cell proliferation, acting through an ATF6-dependent unfolded protein response.

Författare

Jeremie Charbord

Karolinska Institutet

Lipeng Ren

Karolinska Institutet

Rohit B. Sharma

Weill Cornell Medical College

Anna Johansson

Uppsala universitet

Rasmus Ågren

Chalmers, Biologi och bioteknik, Systembiologi, CSBI

Lianhe Chu

Karolinska Institutet

Dominika Tworus

Karolinska Institutet

Nadja Schulz

Karolinska Institutet

Pierre Charbord

Sorbonne Université

Andrew F. Stewart

Icahn School of Medicine at Mount Sinai

Peng Wang

Icahn School of Medicine at Mount Sinai

Laura C. Alonso

Weill Cornell Medical College

Olov Andersson

Karolinska Institutet

NATURE METABOLISM

2522-5812 (eISSN)

Vol. 3 5 682-700

Ämneskategorier

Cellbiologi

Cell- och molekylärbiologi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

DOI

10.1038/s42255-021-00391-x

PubMed

34031592

Mer information

Senast uppdaterat

2021-06-21