TY - JOUR
T1 - IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells
AU - Tsuchiya, Yuichi
AU - Saito, Michiko
AU - Kadokura, Hiroshi
AU - Miyazaki, Jun ichi
AU - Tashiro, Fumi
AU - Imagawa, Yusuke
AU - Iwawaki, Takao
AU - Kohno, Kenji
N1 - Funding Information:
We thank Fumiko Arai and Yusaku Nakamura for contributions to preliminary experimental data, Hitomi Ichikawa for electron microscopy, and Naoko Fujimoto, Junko Iida, Masami Yoshida, Azumi Wada, and Kazumi Maekawa for technical support. We thank Linda Hendershot for the ORP150 antibody, Kenji Inaba for the ERp46 antibody, Kazuhiro Nagata for the PDI family constructs, Toshio Kitamura for retrovirus vectors, and Pedro Herrera for Ins-Cre mice. This work was supported in part by Japan Society for the Promotion of Science KAK ENHI grants JP24228002, JP26116006, and JP17H01468 (to K. Kohno), a Ministry of Education, Culture, Sports, Science and Technology KAK ENHI grant JP19058010 (to K. Kohno), Takeda Science Foundation (to K. Kohno), Japan Society for the Promotion of Science KAK ENHI grant JP26430090 (to M. Saito), Japan Society for the Promotion of Science KAK ENHI grants JP15K07381 and JP26116005 (to H. Kadokura), and Noda Institute for Scientific Research (to H. Kadokura)
Publisher Copyright:
© 2018 Tsuchiya et al.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - In mammalian pancreatic β cells, the IRE1α-XBP1 pathway is constitutively and highly activated under physiological conditions. To elucidate the precise role of this pathway, we constructed β cell-specific Ire1α conditional knockout (CKO) mice and established insulinoma cell lines in which Ire1α was deleted using the Cre-loxP system. Ire1α CKO mice showed the typical diabetic phenotype including impaired glycemic control and defects in insulin biosynthesis postnatally at 4-20 weeks. Ire1α deletion in pancreatic β cells in mice and insulinoma cells resulted in decreased insulin secretion, decreased insulin and proinsulin contents in cells, and decreased oxidative folding of proinsulin along with decreased expression of five protein disulfide isomerases (PDIs): PDI, PDIR, P5, ERp44, and ERp46. Reconstitution of the IRE1α-XBP1 pathway restored the proinsulin and insulin contents, insulin secretion, and expression of the five PDIs, indicating that IRE1α functions as a key regulator of the induction of catalysts for the oxidative folding of proinsulin in pancreatic β cells.
AB - In mammalian pancreatic β cells, the IRE1α-XBP1 pathway is constitutively and highly activated under physiological conditions. To elucidate the precise role of this pathway, we constructed β cell-specific Ire1α conditional knockout (CKO) mice and established insulinoma cell lines in which Ire1α was deleted using the Cre-loxP system. Ire1α CKO mice showed the typical diabetic phenotype including impaired glycemic control and defects in insulin biosynthesis postnatally at 4-20 weeks. Ire1α deletion in pancreatic β cells in mice and insulinoma cells resulted in decreased insulin secretion, decreased insulin and proinsulin contents in cells, and decreased oxidative folding of proinsulin along with decreased expression of five protein disulfide isomerases (PDIs): PDI, PDIR, P5, ERp44, and ERp46. Reconstitution of the IRE1α-XBP1 pathway restored the proinsulin and insulin contents, insulin secretion, and expression of the five PDIs, indicating that IRE1α functions as a key regulator of the induction of catalysts for the oxidative folding of proinsulin in pancreatic β cells.
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U2 - 10.1083/jcb.201707143
DO - 10.1083/jcb.201707143
M3 - Article
C2 - 29507125
AN - SCOPUS:85044776263
VL - 217
SP - 1287
EP - 1301
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 4
ER -
