Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity
Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity
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DOI：
10.1172/jci78863
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发表时间：
2015-05-01
影响因子：
15.9
通讯作者：
Lee, Ann-Hwee
中科院分区：
文献类型：
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作者：
Fedeles, Sorin V.;So, Jae-Seon;Lee, Ann-Hwee
Hsp40辅伴侣SEC63与内质网中的Sec61转位复合体相关。编码SEC63的基因突变会导致人类的多囊肝病；然而，尚不清楚SEC63的改变如何影响疾病的表现。在小鼠中，由于多囊蛋白-1(PC1)的减少，SEC63的缺失导致了肝脏和肾脏的囊性形成。在此，我们报告了SEC63的失活诱导了一条防止包囊形成的未折叠蛋白反应(UPR)途径。具体来说，利用小鼠遗传模型，我们确定SEC63缺乏选择性地激活UPR的IRE1α-XBP1分支，并且SEC63存在于与PC1的复合体中。SEC63和XBP1的同时失活显著抑制了PC1中G蛋白偶联受体蛋白水解点(GPS)的切割，从而加剧了小鼠多囊肾的表型。增强表达剪接的XBP1(XBP1s)增强了SEC63缺陷细胞中PC1的GPS切割，体内过表达XBP1改善了PC1功能降低的小鼠囊性疾病，该模型与SEC63失活无关。综上所述，这些结果表明，SEC63功能调节IRE1α/XBP1的激活，SEC63和XBP1是PC1的GPS切割和成熟所必需的，XBP1的激活可以在PC1生物发生受损的情况下保护其免受多囊疾病的侵袭。
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 Jiver 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 IRE1 alpha-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 IRE1 alpha/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.