Polycystin‐1 dependent regulation of polycystin‐2 via GRP94, a member of HSP90 family that resides in the endoplasmic reticulum

Abstract

Autosomal dominant polycystic kidney disease is a common inherited renal disorder that results from mutations in either PKD1 or PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Downregulation or overexpression of PKD1 or PKD2 in mouse models results in renal cyst formation, suggesting that the quantity of PC1 and PC2 needs to be maintained within a tight functional window to prevent cystogenesis. Here we show that enhanced PC2 expression is a common feature of PKD1 mutant tissues, in part due to an increase in Pkd2 mRNA. However, our data also suggest that more effective protein folding contributes to the augmented levels of PC2. We demonstrate that the unfolded protein response is activated in Pkd1 knockout kidneys and in Pkd1 mutant cells and that this is coupled with increased levels of GRP94, an endoplasmic reticulum protein that is a member of the HSP90 family of chaperones. GRP94 was found to physically interact with PC2 and depletion or chemical inhibition of GRP94 led to a decrease in PC2, suggesting that GRP94 serves as its chaperone. Moreover, GRP94 is acetylated and binds to histone deacetylase 6 (HDAC6), a known deacetylase and activator of HSP90 proteins. Inhibition of HDAC6 decreased PC2 suggesting that HDAC6 and GRP94 work together to regulate PC2 levels. Lastly, we showed that inhibition of GRP94 prevents cAMP-induced cyst formation in vitro. Taken together our data uncovered a novel HDAC6-GRP94-related axis that likely participates in maintaining elevated PC2 levels in Pkd1 mutant cells.

Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease

“…Doxycycline treatment alone, without Pkd gene knockout had no effect on Glis2 expression. Pkd1 mutant primary cells also showed upregulation of Pkd2 transcripts, reproducing another feature of the in vivo TRAP RNASeq and published data 42 (Fig. 3d ).…”

“…The biological relevance of at least some elements of this gene set, which was selected without bias regarding functional roles, is supported by the inclusion of Pkd2 which is significantly upregulated 42 in response to inactivation of Pkd1 in vivo (Fig. 2a–c ).…”

A SEC61A1 variant is associated with autosomal dominant polycystic liver disease

“…Thus, the balance between PC1/PC2 might be important for correct cilia function to prevent polycystic disease. In this complex, PC2 is assumed to be available more abundant 2 and its expression was recently reported to be regulated by ER‐localized chaperones, 46 suggesting that impaired PC2 biosynthesis by decreased SEC61A1‐R236C expression might lead to the polycystic phenotypes observed in the patients described here.…”

Recent advances in understanding ion transport mechanisms in polycystic kidney disease

“…Interestingly, it was suggested that the amount of PC1 and PC2 should be within a certain tight range to prevent cystogenesis. Yao et al recently demonstrated that Pkd1- mutant mouse tissues exhibit increased expression of PC2, which is maintained by a new signaling axis involving histone deacetylase HDAC6 and GRP94 (a member of the HSP90 chaperone family) [ 86 ].…”