KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response.
The endoplasmic reticulum (ER) unfolded protein response (UPR(er)) pathway plays an important role in helping pancreatic β cells to adapt their cellular responses to environmental cues and metabolic stress. Although altered UPR(er) gene expression appears in rodent and human type 2 diabetic (T2D) islets, the underlying molecular mechanisms remain unknown. We show here that germline and β cell-specific disruption of the lysine acetyltransferase 2B (Kat2b) gene in mice leads to impaired insulin secretion and glucose intolerance. Genome-wide analysis of Kat2b-regulated genes and functional assays reveal a critical role for Kat2b in maintaining UPR(er) gene expression and subsequent β cell function. Importantly, Kat2b expression is decreased in mouse and human diabetic β cells and correlates with UPR(er) gene expression in normal human islets. In conclusion, Kat2b is a crucial transcriptional regulator for adaptive β cell function during metabolic stress by controlling UPR(er) and represents a promising target for T2D prevention and treatment.
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Nabil
N
Rabhi
Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
Pierre-Damien
PD
Denechaud
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Xavier
X
Gromada
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Sarah Anissa
SA
Hannou
Laboratory for Integrative and Systems Physiology, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland.
Hongbo
H
Zhang
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Talha
T
Rashid
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Elisabet
E
Salas
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Emmanuelle
E
Durand
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Olivier
O
Sand
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Amélie
A
Bonnefond
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Loic
L
Yengo
Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, 34298 Montpellier, France.
Carine
C
Chavey
University Lille, INSERM, CHU Lille, U1190 - EGID, 59000 Lille, France.
Caroline
C
Bonner
University Lille, INSERM, CHU Lille, U1190 - EGID, 59000 Lille, France.
Julie
J
Kerr-Conte
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
Amar
A
Abderrahmani
Laboratory for Integrative and Systems Physiology, Swiss Federal Institute of Technology, 1015 Lausanne, Switzerland.
Johan
J
Auwerx
Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland.
Lluis
L
Fajas
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France; Departments of Genomics and Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. Electronic address: p.froguel@imperial.ac.uk.
Philippe
P
Froguel
University Lille, UMR 8199 - EGID, 59000 Lille, France; CNRS, UMR 8199, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France. Electronic address: jean-sebastien.annicotte@inserm.fr.
Jean-Sébastien
JS
Annicotte
D000222:Adaptation, Physiological; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D018149:Glucose Intolerance / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000172:deficiency / Q000235:genetics*; D000099224:p300-CBP-Associated Factor
D007328:Insulin; D034741:RNA, Small Interfering; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor