PMID- 29444822
OWN - NLM
STAT- MEDLINE
DCOM- 20190107
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 14
DP  - 2018 Apr 6
TI  - The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein 
      synthesis but by controlling endoplasmic reticulum chaperones.
PG  - 5134-5149
LID - 10.1074/jbc.M117.813790 [doi]
AB  - Loss-of-function mutations of the protein kinase PERK (EIF2AK3) in humans and 
      mice cause permanent neonatal diabetes and severe proinsulin aggregation in the 
      endoplasmic reticulum (ER), highlighting the essential role of PERK in insulin 
      production in pancreatic beta cells. As PERK is generally known as a translational 
      regulator of the unfolded protein response (UPR), the underlying cause of these beta 
      cell defects has often been attributed to derepression of proinsulin synthesis, 
      resulting in proinsulin overload in the ER. Using high-resolution imaging and 
      standard protein fractionation and immunological methods we have examined the 
      PERK-dependent phenotype more closely. We found that whereas proinsulin 
      aggregation requires new protein synthesis, global protein and proinsulin 
      synthesis are down-regulated in PERK-inhibited cells, strongly arguing against 
      proinsulin overproduction being the root cause of their aberrant ER phenotype. 
      Furthermore, we show that PERK regulates proinsulin proteostasis by modulating ER 
      chaperones, including BiP and ERp72. Transgenic overexpression of BiP and BiP 
      knockdown (KD) both promoted proinsulin aggregation, whereas ERp72 overexpression 
      and knockdown rescued it. These findings underscore the importance of ER 
      chaperones working in concert to achieve control of insulin production and 
      identify a role for PERK in maintaining a functional balance among these 
      chaperones.
CI  - (c) 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Sowers, Carrie R
AU  - Sowers CR
AD  - From the Department of Biology, Penn State University, University Park, 
      Pennsylvania 16802.
FAU - Wang, Rong
AU  - Wang R
AD  - From the Department of Biology, Penn State University, University Park, 
      Pennsylvania 16802.
FAU - Bourne, Rebecca A
AU  - Bourne RA
AD  - From the Department of Biology, Penn State University, University Park, 
      Pennsylvania 16802.
FAU - McGrath, Barbara C
AU  - McGrath BC
AD  - From the Department of Biology, Penn State University, University Park, 
      Pennsylvania 16802.
FAU - Hu, Jingjie
AU  - Hu J
AD  - From the Department of Biology, Penn State University, University Park, 
      Pennsylvania 16802.
FAU - Bevilacqua, Sarah C
AU  - Bevilacqua SC
AD  - From the Department of Biology, Penn State University, University Park, 
      Pennsylvania 16802.
FAU - Paton, James C
AU  - Paton JC
AD  - the Department of Molecular and Cellular Biology, Research Centre for Infectious 
      Diseases, University of Adelaide, Adelaide 5005, Australia.
FAU - Paton, Adrienne W
AU  - Paton AW
AD  - the Department of Molecular and Cellular Biology, Research Centre for Infectious 
      Diseases, University of Adelaide, Adelaide 5005, Australia.
FAU - Collardeau-Frachon, Sophie
AU  - Collardeau-Frachon S
AUID- ORCID: 0000-0001-8604-1089
AD  - the Department of Pathology, Hopital-Femme-Mere-Enfant, Hospices Civils de Lyon, 
      Universite Claude Bernard Lyon I and CarMeN, INSERM Unit U1060, 69677 Bron, 
      France, and.
FAU - Nicolino, Marc
AU  - Nicolino M
AUID- ORCID: 0000-0001-5395-2249
AD  - the Service d'endocrinologie et de diabetologie pediatriques et maladies 
      hereditaires du metabolisme, Hopital Femme-Mere-Enfant, Hospices Civils de Lyon, 
      F-69677 Bron, France.
FAU - Cavener, Douglas R
AU  - Cavener DR
AUID- ORCID: 0000-0002-1558-7137
AD  - From the Department of Biology, Penn State University, University Park, 
      Pennsylvania 16802, drc9@psu.edu.
LA  - eng
GR  - R01 DK088140/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180214
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Insulin)
RN  - 0 (Molecular Chaperones)
RN  - 9035-68-1 (Proinsulin)
RN  - EC 2.7.11.1 (EIF2AK3 protein, human)
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - IY9XDZ35W2 (Glucose)
RN  - Diabetes Mellitus, Permanent Neonatal
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus/metabolism
MH  - Endoplasmic Reticulum/physiology
MH  - Glucose/metabolism
MH  - Humans
MH  - Insulin/metabolism
MH  - Insulin-Secreting Cells/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Molecular Chaperones/metabolism
MH  - Proinsulin/genetics/*metabolism
MH  - Protein Biosynthesis/drug effects
MH  - Unfolded Protein Response/drug effects
MH  - eIF-2 Kinase/genetics/*metabolism
PMC - PMC5892574
OTO - NOTNLM
OT  - BiP
OT  - PERK
OT  - beta cells
OT  - chaperone
OT  - endoplasmic reticulum (ER)
OT  - insulin secretion
OT  - intracellular trafficking
OT  - protein aggregation
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2018/02/16 06:00
MHDA- 2019/01/08 06:00
PMCR- 2019/04/06
CRDT- 2018/02/16 06:00
PHST- 2017/08/21 00:00 [received]
PHST- 2018/02/06 00:00 [revised]
PHST- 2018/02/16 06:00 [pubmed]
PHST- 2019/01/08 06:00 [medline]
PHST- 2018/02/16 06:00 [entrez]
PHST- 2019/04/06 00:00 [pmc-release]
AID - S0021-9258(20)40987-1 [pii]
AID - M117.813790 [pii]
AID - 10.1074/jbc.M117.813790 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Apr 6;293(14):5134-5149. doi: 10.1074/jbc.M117.813790. Epub 
      2018 Feb 14.