Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
Year: 2023
Type: article
Abstract: Fibrocystin/Polyductin (FPC) is encoded by PKHD1 which, when mutated, causes autosomal recessive polycystic kidney disease (ARPKD). FPC’s function and its role in cystogenesis are unknown. We describe that endogenous FPC undergoes complex proteolytic processing, generating three small C-terminal fragments (ICDs), one of which (ICD15) contains a novel mitochondrial targeting sequence that directs its translocation into mitochondria. Pkhd1 inactivation leads to aberrant ultrastructural morphology of mitochondria in proximal tubules of developing kidneys. FPC inactivation enhances renal cystogenesis and causes severe pancreatic cystogenesis in a Pkd1 mouse mutant with blocked G protein‐coupled receptor proteolysis site (GPS) cleavage of the Pkd1-encoded Polycystin-1 protein. Deletion of the ICD15 region, encoded by exon 67, is sufficient to enhance renal cystogenesis but does not cause pancreatic cystogenesis. Our results connect FPC, a ciliary protein, directly to a mitochondrial signaling pathway whose perturbation is implicated in PKD pathogenesis.
Source: Nature Communications
Authors: Rebecca V Walker, Qin Yao, Hangxue Xu, Anthony Maranto, Kristen F Swaney, Sreekumar Ramachandran, Rong Li, Laura Cassina, Brian M Polster, Patricia Outeda, Alessandra Boletta, Terry Watnick, Feng Qian
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Awards: The Molecular Mechanisms of Polycystin-1 Proteolytic Cleavage in Kidney Health and Polycystic Kidney Disease, Baltimore Polycystic Kidney Disease Research and Clinical Core Center, Ion Channel Function and Regulation of the Polycystin-1/2 Complex in Kidney Physiology and Polycystic Kidney Disease, Maryland Polycystic Kidney Disease Research Core Center (MPKD-RCC)
OpenAlex ID: W4387692181