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Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity
Sorin V. Fedeles, … , Stefan Somlo, Ann-Hwee Lee
Sorin V. Fedeles, … , Stefan Somlo, Ann-Hwee Lee
Published April 6, 2015
Citation Information: J Clin Invest. 2015;125(5):1955-1967. https://doi.org/10.1172/JCI78863.
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Research Article Nephrology

Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity

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Abstract

The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1). Here we report that inactivation of SEC63 induces an unfolded protein response (UPR) pathway that is protective against cyst formation. Specifically, using murine genetic models, we determined that SEC63 deficiency selectively activates the IRE1α-XBP1 branch of UPR and that SEC63 exists in a complex with PC1. Concomitant inactivation of both SEC63 and XBP1 exacerbated the polycystic kidney phenotype in mice by markedly suppressing cleavage at the G protein–coupled receptor proteolysis site (GPS) in PC1. Enforced expression of spliced XBP1 (XBP1s) enhanced GPS cleavage of PC1 in SEC63-deficient cells, and XBP1 overexpression in vivo ameliorated cystic disease in a murine model with reduced PC1 function that is unrelated to SEC63 inactivation. Collectively, the findings show that SEC63 function regulates IRE1α/XBP1 activation, SEC63 and XBP1 are required for GPS cleavage and maturation of PC1, and activation of XBP1 can protect against polycystic disease in the setting of impaired biogenesis of PC1.

Authors

Sorin V. Fedeles, Jae-Seon So, Amol Shrikhande, Seung Hun Lee, Anna-Rachel Gallagher, Christina E. Barkauskas, Stefan Somlo, Ann-Hwee Lee

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Figure 1

SEC63 deficiency activates IRE1α-XBP1 but not other UPR branches.

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SEC63 deficiency activates IRE1α-XBP1 but not other UPR branches.
(A) Xb...
(A) Xbp1 mRNA RT-PCR splicing assay in Sec63- or Prkcsh-deficient cells and kidney tissues. Spliced XBP1s is only present in SEC63-KO cells and kidneys. (B) WT (Sec63fl/fl), SEC63-KO cells, and SEC63-KO cells reconstituted with SEC63 or GFP in the unstressed state or were treated with tunicamycin (Tun; 2 μg/ml) or thapsigargin (Thap; 1 μM) for 4 hours. IRE1α and PERK activation (phosphorylation) was analyzed by immunoblotting. Phos-tag electrophoresis was performed to better separate p-IRE1α from the unphosphorylated form. (C) WT and SEC63-KO cells in the basal state or treated with tunicamycin for the indicated times. UPR activation analyzed by immunoblotting with indicated antibodies. (D and E) Quantitative RT-PCR expression of UPR marker genes in SEC63-KO and the reconstituted cells (D, n = 3 per group), and SEC63-KO P18 kidneys (E, n = 6–8 mice per group). (F) Kidney nuclear extracts examined by immunoblotting with indicated antibodies. Tunicamycin-treated (1 mg/kg, 6 hours) mice were used as positive controls. ns, a nonspecific band used for loading control. (G) eIF2α phosphorylation was determined by immunoblot using whole kidney lysates. Note the residual SEC63 expression in SEC63-KO kidneys due to the cell type–specific expression of Ksp-Cre. Results are shown as mean ± SEM (Student’s t test); ***P < 0.001; **P < 0.01, *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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