Altered trafficking and stability of polycystins underlie polycystic kidney disease

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

“…31 Consistently, reduction of PI3K-C2a levels exacerbated spontaneous cyst formation also in a Pkd1 heterozygous background. Given that polycystin-1 and -2 mutually influence their ciliary translocation from the Golgi apparatus, 41,42 enhanced cystogenesis in Pik3c2a +/2 ;Pkd2 +/2 mice is in agreement with an effect of PI3K-C2a on the ciliary trafficking of both proteins of the polycystin dimer.…”

Isolated polycystic liver disease genes define effectors of polycystin-1 function

“…ALG8 (asparagine-linked glycosylation 8) encodes α-1,3-glucosyltransferase, an ER integral membrane protein that functions to add the second of 3 glucoses to the assembling lipidlinked oligosaccharide precursor for N-linked glycosylation before it is transferred to the nascent peptide (38). ALG8 intersects with the protein biogenesis pathway between the sites of action of proteolysis site (GPS) into an approximately 3,000-amino acid extracellular N-terminal fragment (PC1-NTF) and an approximately 1,300-amino acid intramembranous C-terminal fragment (PC1-CTF) (34,35). PC1-NTF migrates as 2 protein species -the cell surface-expressed endoglycosidase H-resistant (EndoHresistant) PC1-NTR and the intracellular EndoH-sensitive PC1-NTS (36,37).…”

Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity

“…The mechanism underlying the worsening polycystic phenotype in the DKO is a significant reduction of PC1 GPS cleavage without further reduction in steadystate PC1 protein expression compared with the SEC63-KO. We recently found that GPS cleavage is essential for PC1 trafficking to cilia and to its function in vivo (19). In keeping with the DKO phenotype being PC1 dependent, the worsening polycystic kidney disease is primarily the result of increased cyst-cell proliferation in the collecting duct, the nephron segment that has proved to be most sensitive to PC1 dosage in vivo (14).…”

“…The GPS undergoes autoproteolytic cleavage (16) via a GPCR autoproteolysis-inducing (GAIN) domain with a structure that was recently solved (17). Knock-in mice producing noncleavable PC1 develop cystic kidneys (18), and GPS cleavage-deficient PC1 protein does not traffic properly and has complete loss of function (19), highlighting the critical role of GPS cleavage in PC1 functionality.…”