Polycystin-2 down-regulates cell proliferation via promoting PERK-dependent phosphorylation of eIF2α

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of renal, hepatic and pancreatic cysts and by non-cystic manifestations such as abnormal vasculature and embryo left-right asymmetry development. Polycystin-2 (PC2), in which mutations account for 10-15% of ADPKD, was previously shown to down-regulate cell proliferation, but the underlying mechanism was not elucidated. Here, we demonstrate that PC2, but not pathogenic mutants E837X and R872X, represses cell proliferation through promoting the phosphorylation of eukaryotic translation initiation factor eIF2alpha by pancreatic ER-resident eIF2alpha kinase (PERK). ER stress is known to enhance eIF2alpha phosphorylation through up-regulating PERK kinase activity (assessed by phosphorylated PERK). During ER stress, PC2 knockdown also repressed eIF2alpha phosphorylation but did not alter PERK phosphorylation, indicating that PC2 facilitates the eIF2alpha phosphorylation by PERK. PC2 was found to be in the same complex as PERK and eIF2alpha. Together, we demonstrate that PC2 negatively controls cell growth by promoting PERK-mediated eIF2alpha phosphorylation, presumably through physical interaction, which may underlie a pathogenesis mechanism of ADPKD and indicates that PC2 is an important regulator of the translation machinery.

Polycystin-1 Negatively Regulates Polycystin-2 Expression via the Aggresome/Autophagosome Pathway

“…PC2 expression has a negative effect on cell proliferation in cell culture models (40,41), whereas PC2 overexpression in animal models leads to cyst formation (42), suggesting that the level of PC2 must be tightly controlled to prevent cyst formation. It is possible that tight regulation of PC2 as well as PC1 is required to prevent cyst formation.…”

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“…16,22,24 Coimmunoprecipitation, membrane fractionation, and Western blot analyses were performed as described previously. 16,22,24,28 …”