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Protective unfolded protein response in human pancreatic beta cells transplanted into mice

ABSTRACT: Islet transplantation exposes beta cells to mild hyperglycemia and to the abnormal environment of the transplant site. These conditions may affect beta cells and induce the expression of genes involved in beta cell damage. Gene expression profile of human beta cells exposed to mild hyperglycemia by transplantation into ICR-SCID mice was evaluated and compared with the gene profile of beta cells obtained from non-diabetic subjects. We found that the transplanted beta cells showed an unfolded protein response (UPR). There was upregulation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress. Among them, increased expression of genes coding XBP-1; the chaperone proteins PDIA4, Bip, and Grp94; and the ER degradation proteins EDEM1 and EDEM2. ERdj4 and DNA-JC3 were also upregulated. JUK had downregulated expression. The PERK and ATF-6 arms of the ER stress response had many downregulated genes in transplanted islets. The PERK's substrates, EIF2A and NRF2, showed markedly reduced expression, as downregulated was the expression of CReP. Other downregulated genes included HERP2, IRS-2, CHOP and C/EBP-beta. In the transplanted beta cells there was significantly decreased expression of ATF-6, as well as the downstream gene products CHOP and HERP2. There was increased expression of HRD1, which exerts an antiapoptotic effect by degrading unfolded proteins. In conclusion human beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptotic effects of unfolded proteins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22097 | GEO | 2010/06/02

SECONDARY ACCESSION(S): PRJNA128915

REPOSITORIES: GEO

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Project description:A data-entrained computational model for testing the regulatory logic of the vertebrate unfolded protein response This model is described in the article: A data-entrained computational model for testing the regulatory logic of the vertebrate unfolded protein response. Diedrichs DR, Gomez JA, Huang CS, Rutkowski DT, Curtu R. Mol. Biol. Cell 2018 Apr; : mbcE17090565 Abstract: The vertebrate unfolded protein response (UPR) is characterized by multiple interacting nodes among its three pathways, yet the logic underlying this regulatory complexity is unclear. To begin to address this issue, we created a computational model of the vertebrate UPR that was entrained upon and then validated against experimental data. As part of this validation, the model successfully predicted the phenotypes of cells with lesions in UPR signaling, including a surprising and previously unreported differential role for the eIF2? phosphatase GADD34 in exacerbating severe stress but ameliorating mild stress. We then used the model to test the functional importance of a feed-forward circuit within the PERK/CHOP axis, and of cross-regulatory control of BiP and CHOP expression. We found that the wiring structure of the UPR appears to balance the ability of the response to remain sensitive to ER stress yet also to be rapidly deactivated by improved protein folding conditions. This model should serve as a valuable resource for further exploring the regulatory logic of the UPR. This model is hosted on BioModels Database and identified by: MODEL1803300000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Protective unfolded protein response in human pancreatic beta cells transplanted into mice

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