Polycystin-1, the product of the polycystic kidney disease gene PKD1, is post-translationally modified by palmitoylation.

Multiple distinct mutations in the protein polycystin 1 (PC1) cause autosomal dominant polycystic kidney disease (ADPKD), a common cause of end stage renal disease. Growing evidence supports the theory that the severity and rate of progression of kidney cysts is correlated with the level of functional PC1 expressed in the primary cilia. Factors that regulate trafficking of PC1 to cilia are thus of great interest both as potential causes of ADPKD, but also as possible modifiable factors to treat ADPKD. Cysteine palmitoylation is a common post-translational modification that frequently alters protein trafficking, localization, and expression levels. Here, using multiple complementary approaches, we show that PC1 is palmitoylated, likely at a single cysteine in the carboxyl terminal fragment that is generated by autoproteolysis of PC1. Additional data suggest that protein palmitoylation is important for PC1 localization and expression levels. These data together identify palmitoylation as a novel post-translational modification of PC1 and a possible pharmacologic target to augment PC1 expression in cilia.