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Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis

Primary cilia play counterregulatory roles in cystogenesis—they inhibit cyst formation in the normal renal tubule but promote cyst growth when the function of polycystins is impaired. Key upstream cilia-specific signals and components involved in driving cystogenesis have remained elusive. Recent st...

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Autores principales: Walker, Rebecca V., Maranto, Anthony, Palicharla, Vivek Reddy, Hwang, Sun-Hee, Mukhopadhyay, Saikat, Qian, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272769/
https://www.ncbi.nlm.nih.gov/pubmed/35832738
http://dx.doi.org/10.3389/fmolb.2022.936070
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author Walker, Rebecca V.
Maranto, Anthony
Palicharla, Vivek Reddy
Hwang, Sun-Hee
Mukhopadhyay, Saikat
Qian, Feng
author_facet Walker, Rebecca V.
Maranto, Anthony
Palicharla, Vivek Reddy
Hwang, Sun-Hee
Mukhopadhyay, Saikat
Qian, Feng
author_sort Walker, Rebecca V.
collection PubMed
description Primary cilia play counterregulatory roles in cystogenesis—they inhibit cyst formation in the normal renal tubule but promote cyst growth when the function of polycystins is impaired. Key upstream cilia-specific signals and components involved in driving cystogenesis have remained elusive. Recent studies of the tubby family protein, Tubby-like protein 3 (TULP3), have provided new insights into the cilia-localized mechanisms that determine cyst growth. TULP3 is a key adapter of the intraflagellar transport complex A (IFT-A) in the trafficking of multiple proteins specifically into the ciliary membrane. Loss of TULP3 results in the selective exclusion of its cargoes from cilia without affecting their extraciliary pools and without disrupting cilia or IFT-A complex integrity. Epistasis analyses have indicated that TULP3 inhibits cystogenesis independently of the polycystins during kidney development but promotes cystogenesis in adults when polycystins are lacking. In this review, we discuss the current model of the cilia-dependent cyst activation (CDCA) mechanism in autosomal dominant polycystic kidney disease (ADPKD) and consider the possible roles of ciliary and extraciliary polycystins in regulating CDCA. We then describe the limitations of this model in not fully accounting for how cilia single knockouts cause significant cystic changes either in the presence or absence of polycystins. Based on available data from TULP3/IFT-A-mediated differential regulation of cystogenesis in kidneys with deletion of polycystins either during development or in adulthood, we hypothesize the existence of cilia-localized components of CDCA (cCDCA) and cilia-localized cyst inhibition (CLCI) signals. We develop the criteria for cCDCA/CLCI signals and discuss potential TULP3 cargoes as possible cilia-localized components that determine cystogenesis in kidneys during development and in adult mice.
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spelling pubmed-92727692022-07-12 Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis Walker, Rebecca V. Maranto, Anthony Palicharla, Vivek Reddy Hwang, Sun-Hee Mukhopadhyay, Saikat Qian, Feng Front Mol Biosci Molecular Biosciences Primary cilia play counterregulatory roles in cystogenesis—they inhibit cyst formation in the normal renal tubule but promote cyst growth when the function of polycystins is impaired. Key upstream cilia-specific signals and components involved in driving cystogenesis have remained elusive. Recent studies of the tubby family protein, Tubby-like protein 3 (TULP3), have provided new insights into the cilia-localized mechanisms that determine cyst growth. TULP3 is a key adapter of the intraflagellar transport complex A (IFT-A) in the trafficking of multiple proteins specifically into the ciliary membrane. Loss of TULP3 results in the selective exclusion of its cargoes from cilia without affecting their extraciliary pools and without disrupting cilia or IFT-A complex integrity. Epistasis analyses have indicated that TULP3 inhibits cystogenesis independently of the polycystins during kidney development but promotes cystogenesis in adults when polycystins are lacking. In this review, we discuss the current model of the cilia-dependent cyst activation (CDCA) mechanism in autosomal dominant polycystic kidney disease (ADPKD) and consider the possible roles of ciliary and extraciliary polycystins in regulating CDCA. We then describe the limitations of this model in not fully accounting for how cilia single knockouts cause significant cystic changes either in the presence or absence of polycystins. Based on available data from TULP3/IFT-A-mediated differential regulation of cystogenesis in kidneys with deletion of polycystins either during development or in adulthood, we hypothesize the existence of cilia-localized components of CDCA (cCDCA) and cilia-localized cyst inhibition (CLCI) signals. We develop the criteria for cCDCA/CLCI signals and discuss potential TULP3 cargoes as possible cilia-localized components that determine cystogenesis in kidneys during development and in adult mice. Frontiers Media S.A. 2022-06-23 /pmc/articles/PMC9272769/ /pubmed/35832738 http://dx.doi.org/10.3389/fmolb.2022.936070 Text en Copyright © 2022 Walker, Maranto, Palicharla, Hwang, Mukhopadhyay and Qian. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Walker, Rebecca V.
Maranto, Anthony
Palicharla, Vivek Reddy
Hwang, Sun-Hee
Mukhopadhyay, Saikat
Qian, Feng
Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis
title Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis
title_full Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis
title_fullStr Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis
title_full_unstemmed Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis
title_short Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis
title_sort cilia-localized counterregulatory signals as drivers of renal cystogenesis
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272769/
https://www.ncbi.nlm.nih.gov/pubmed/35832738
http://dx.doi.org/10.3389/fmolb.2022.936070
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