scholarly journals Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins

2017 ◽  
Vol 216 (3) ◽  
pp. 743-760 ◽  
Author(s):  
Hemant B. Badgandi ◽  
Sun-hee Hwang ◽  
Issei S. Shimada ◽  
Evan Loriot ◽  
Saikat Mukhopadhyay
Keyword(s):  
Kidney Disease ◽  
Membrane Proteins ◽  
Polycystic Kidney Disease ◽  
Protein Trafficking ◽  
Intraflagellar Transport ◽  
Integral Membrane Proteins ◽  
Dependent Manner ◽  
Polycystic Kidney ◽  
Neuronal Cilia ◽  
Step Model

The primary cilium is a paradigmatic organelle for studying compartmentalized signaling; however, unlike soluble protein trafficking, processes targeting integral membrane proteins to cilia are poorly understood. In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein–coupled receptors (GPCRs) and the polycystic kidney disease–causing polycystin 1/2 complex. The founding tubby family member TUB also localizes to cilia similar to TULP3 and determines trafficking of a subset of these GPCRs to neuronal cilia. Using minimal ciliary localization sequences from GPCRs and fibrocystin (also implicated in polycystic kidney disease), we demonstrate these motifs to be sufficient and TULP3 dependent for ciliary trafficking. We propose a three-step model for TULP3/TUB-mediated ciliary trafficking, including the capture of diverse membrane cargo by the tubby domain in a phosphoinositide 4,5-bisphosphate (PI(4,5)P2)-dependent manner, ciliary delivery by intraflagellar transport complex A binding to the TULP3/TUB N terminus, and subsequent release into PI(4,5)P2-deficient ciliary membrane.

scholarly journals Obacunone Retards Renal Cyst Development in Autosomal Dominant Polycystic Kidney Disease by Activating NRF2

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 38
Author(s):  
Zhiwei Qiu ◽  
Jinzhao He ◽  
Guangying Shao ◽  
Jiaqi Hu ◽  
Xiaowei Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Renal Cyst ◽  
Renal Diseases ◽  
Therapeutic Drug ◽  
Dependent Manner ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Development

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The purpose of this study was to discover an effective therapeutic drug for ADPKD. With virtual screening, Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney-specific Pkd1 knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library. In vitro experiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner. In vivo, obacunone treatment significantly reduced the renal cyst development in PKD mice. Western blot and morphological analysis revealed that obacunone served as a NRF2 activator in ADPKD, which suppressed lipid peroxidation by up-regulating GPX4 and finally restrained excessive cell proliferation by down-regulating mTOR and MAPK signaling pathways. Experimental data demonstrated obacunone as an effective renal cyst inhibitor for ADPKD, indicating that obacunone might be developed into a therapeutic drug for ADPKD treatment.

scholarly journals Function and dynamics of PKD2 in Chlamydomonas reinhardtii flagella

2007 ◽  
Vol 179 (3) ◽  
pp. 501-514 ◽  
Author(s):  
Kaiyao Huang ◽  
Dennis R. Diener ◽  
Aaron Mitchell ◽  
Gregory J. Pazour ◽  
George B. Witman ◽  
...  
Keyword(s):  
Rna Interference ◽  
Kidney Disease ◽  
Chlamydomonas Reinhardtii ◽  
Polycystic Kidney Disease ◽  
Fluorescence Recovery After Photobleaching ◽  
Intraflagellar Transport ◽  
Polycystic Kidney ◽  
Gene Encoding ◽  
Whole Cells ◽  
Flagellar Membrane

To analyze the function of ciliary polycystic kidney disease 2 (PKD2) and its relationship to intraflagellar transport (IFT), we cloned the gene encoding Chlamydomonas reinhardtii PKD2 (CrPKD2), a protein with the characteristics of PKD2 family members. Three forms of this protein (210, 120, and 90 kD) were detected in whole cells; the two smaller forms are cleavage products of the 210-kD protein and were the predominant forms in flagella. In cells expressing CrPKD2–GFP, about 10% of flagellar CrPKD2–GFP was observed moving in the flagellar membrane. When IFT was blocked, fluorescence recovery after photobleaching of flagellar CrPKD2–GFP was attenuated and CrPKD2 accumulated in the flagella. Flagellar CrPKD2 increased fourfold during gametogenesis, and several CrPKD2 RNA interference strains showed defects in flagella-dependent mating. These results suggest that the CrPKD2 cation channel is involved in coupling flagellar adhesion at the beginning of mating to the increase in flagellar calcium required for subsequent steps in mating.

scholarly journals Autosomal Dominant Polycystic Kidney Disease and Hypertension are Associated with Left Ventricular Mass in a Gender-Dependent Manner

2012 ◽  
Vol 36 (1) ◽  
pp. 301-309 ◽  
Author(s):  
Maria Pietrzak-Nowacka ◽  
Krzysztof Safranow ◽  
Malgorzata Czechowska ◽  
Grazyna Dutkiewicz ◽  
Zdzislawa Kornacewicz-Jach ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Left Ventricular Mass ◽  
Autosomal Dominant ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Polycystic Kidney ◽  
Ventricular Mass ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals CD2-associated protein directly interacts with the actin cytoskeleton

2002 ◽  
Vol 283 (4) ◽  
pp. F734-F743 ◽  
Author(s):  
Sanna Lehtonen ◽  
Fang Zhao ◽  
Eero Lehtonen
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Disease ◽  
Membrane Proteins ◽  
Actin Cytoskeleton ◽  
Polycystic Kidney Disease ◽  
Cultured Cells ◽  
Congenital Nephrotic Syndrome ◽  
Filamentous Actin ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

CD2-associated protein (CD2AP) is an adapter protein associating with several membrane proteins, including nephrin, mutated in congenital nephrotic syndrome of the Finnish type, and polycystin-2, mutated in type 2 autosomal dominant polycystic kidney disease. Both proteins have critical roles in the maintenance of the integrity of the nephrons. Previous studies have suggested a role for CD2AP in the regulation of the organization of the actin cytoskeleton, but it has not been known whether the postulated association between CD2AP and actin is direct or mediated by other proteins. In this study, we address this question by using various cellular and biochemical approaches. We show that CD2AP and F-actin partially colocalize in cultured cells and that disruption of the actin cytoskeleton results in disorganization of endogenous CD2AP. Using cytoskeletal fractionation by differential centrifugation, we demonstrate that a proportion of CD2AP associates with the actin cytoskeleton. Furthermore, using pure actin and purified CD2AP fusion proteins in an F-actin coprecipitation assay, we show that CD2AP directly associates with filamentous actin and that this interaction is mediated by means of the COOH terminus of CD2AP. The present results suggest that CD2AP is involved in the regulation of the actin cytoskeleton and indicate that CD2AP may act as a direct adapter between the actin cytoskeleton and cell membrane proteins, such as nephrin and polycystin-2. Alterations in these interactions could explain some of the pathophysiological changes in congenital nephrotic syndrome and polycystic kidney disease.

scholarly journals Chlamydomonas IFT88 and Its Mouse Homologue, Polycystic Kidney Disease Gene Tg737, Are Required for Assembly of Cilia and Flagella

2000 ◽  
Vol 151 (3) ◽  
pp. 709-718 ◽  
Author(s):  
Gregory J. Pazour ◽  
Bethany L. Dickert ◽  
Yvonne Vucica ◽  
E. Scott Seeley ◽  
Joel L. Rosenbaum ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Disease Gene ◽  
Intraflagellar Transport ◽  
Polycystic Kidney ◽  
Subunit Protein ◽  
Human Genes ◽  
Protein Particles ◽  
Cilia And Flagella

Intraflagellar transport (IFT) is a rapid movement of multi-subunit protein particles along flagellar microtubules and is required for assembly and maintenance of eukaryotic flagella. We cloned and sequenced a Chlamydomonas cDNA encoding the IFT88 subunit of the IFT particle and identified a Chlamydomonas insertional mutant that is missing this gene. The phenotype of this mutant is normal except for the complete absence of flagella. IFT88 is homologous to mouse and human genes called Tg737. Mice with defects in Tg737 die shortly after birth from polycystic kidney disease. We show that the primary cilia in the kidney of Tg737 mutant mice are shorter than normal. This indicates that IFT is important for primary cilia assembly in mammals. It is likely that primary cilia have an important function in the kidney and that defects in their assembly can lead to polycystic kidney disease.

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