NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology
Abstract Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births. The major clinical phenotypes are expressed in the kidney with dilatation of the collecting ducts, systemic hypertension, and progressive renal insufficiency, and...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/89f3879b5d154e2796418eb76debe918 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:89f3879b5d154e2796418eb76debe918 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:89f3879b5d154e2796418eb76debe9182021-12-02T15:05:11ZNEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology10.1038/s41598-017-08284-42045-2322https://doaj.org/article/89f3879b5d154e2796418eb76debe9182017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08284-4https://doaj.org/toc/2045-2322Abstract Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births. The major clinical phenotypes are expressed in the kidney with dilatation of the collecting ducts, systemic hypertension, and progressive renal insufficiency, and in the liver with biliary dysgenesis, portal tract fibrosis, and portal hypertension. The systemic hypertension has been attributed to enhanced distal sodium reabsorption in the kidney, the structural defects have been ascribed to altered cellular morphology, and fibrosis to increased TGF-β signaling in the kidney and biliary tract, respectively. The pathogenic mechanisms underlying these abnormalities have not been determined. In the current report, we find that disrupting PKHD1 results in altered sub-cellular localization and function of the C2-WWW-HECT domain E3 family of ligases regulating these processes. We also demonstrate altered activity of RhoA and increased TGF-β signaling and ENaC activity. Linking these phenomena, we found that vesicles containing the PKHD1/Pkhd1 gene product, FPC, also contain the NEDD4 ubiquitin ligase interacting protein, NDFIP2, which interacts with multiple members of the C2-WWW-HECT domain E3 family of ligases. Our results provide a mechanistic explanation for both the cellular effects and in vivo phenotypic abnormalities in mice and humans that result from Pkhd1/PKHD1 mutation.Jun-ya KaimoriCheng-Chao LinPatricia OutedaMiguel A. Garcia-GonzalezLuis F. MenezesErum A. HartungAo LiGuanqing WuHideaki FujitaYasunori SatoYasuni NakanumaSatoko YamamotoNaotsugu IchimaruShiro TakaharaYoshitaka IsakaTerry WatnickLuiz F. OnuchicLisa M. Guay-WoodfordGregory G. GerminoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Jun-ya Kaimori Cheng-Chao Lin Patricia Outeda Miguel A. Garcia-Gonzalez Luis F. Menezes Erum A. Hartung Ao Li Guanqing Wu Hideaki Fujita Yasunori Sato Yasuni Nakanuma Satoko Yamamoto Naotsugu Ichimaru Shiro Takahara Yoshitaka Isaka Terry Watnick Luiz F. Onuchic Lisa M. Guay-Woodford Gregory G. Germino NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology |
| description |
Abstract Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births. The major clinical phenotypes are expressed in the kidney with dilatation of the collecting ducts, systemic hypertension, and progressive renal insufficiency, and in the liver with biliary dysgenesis, portal tract fibrosis, and portal hypertension. The systemic hypertension has been attributed to enhanced distal sodium reabsorption in the kidney, the structural defects have been ascribed to altered cellular morphology, and fibrosis to increased TGF-β signaling in the kidney and biliary tract, respectively. The pathogenic mechanisms underlying these abnormalities have not been determined. In the current report, we find that disrupting PKHD1 results in altered sub-cellular localization and function of the C2-WWW-HECT domain E3 family of ligases regulating these processes. We also demonstrate altered activity of RhoA and increased TGF-β signaling and ENaC activity. Linking these phenomena, we found that vesicles containing the PKHD1/Pkhd1 gene product, FPC, also contain the NEDD4 ubiquitin ligase interacting protein, NDFIP2, which interacts with multiple members of the C2-WWW-HECT domain E3 family of ligases. Our results provide a mechanistic explanation for both the cellular effects and in vivo phenotypic abnormalities in mice and humans that result from Pkhd1/PKHD1 mutation. |
| format |
article |
| author |
Jun-ya Kaimori Cheng-Chao Lin Patricia Outeda Miguel A. Garcia-Gonzalez Luis F. Menezes Erum A. Hartung Ao Li Guanqing Wu Hideaki Fujita Yasunori Sato Yasuni Nakanuma Satoko Yamamoto Naotsugu Ichimaru Shiro Takahara Yoshitaka Isaka Terry Watnick Luiz F. Onuchic Lisa M. Guay-Woodford Gregory G. Germino |
| author_facet |
Jun-ya Kaimori Cheng-Chao Lin Patricia Outeda Miguel A. Garcia-Gonzalez Luis F. Menezes Erum A. Hartung Ao Li Guanqing Wu Hideaki Fujita Yasunori Sato Yasuni Nakanuma Satoko Yamamoto Naotsugu Ichimaru Shiro Takahara Yoshitaka Isaka Terry Watnick Luiz F. Onuchic Lisa M. Guay-Woodford Gregory G. Germino |
| author_sort |
Jun-ya Kaimori |
| title |
NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology |
| title_short |
NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology |
| title_full |
NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology |
| title_fullStr |
NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology |
| title_full_unstemmed |
NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology |
| title_sort |
nedd4-family e3 ligase dysfunction due to pkhd1/pkhd1 defects suggests a mechanistic model for arpkd pathobiology |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/89f3879b5d154e2796418eb76debe918 |
| work_keys_str_mv |
AT junyakaimori nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT chengchaolin nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT patriciaouteda nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT miguelagarciagonzalez nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT luisfmenezes nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT erumahartung nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT aoli nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT guanqingwu nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT hideakifujita nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT yasunorisato nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT yasuninakanuma nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT satokoyamamoto nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT naotsuguichimaru nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT shirotakahara nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT yoshitakaisaka nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT terrywatnick nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT luizfonuchic nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT lisamguaywoodford nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology AT gregoryggermino nedd4familye3ligasedysfunctionduetopkhd1pkhd1defectssuggestsamechanisticmodelforarpkdpathobiology |
| _version_ |
1718388903245774848 |