Lack of ANKMY2 suppresses kidney cystogenesis in embryonic-and adult-onset polycystic kidney disease

Sep 29, 2026

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Autosomal dominant polycystic kidney disease (ADPKD) drives progressive, bilateral cyst formation, yet the initiating mechanisms remain unclear. Multiple dysregulated pathways, including cAMP signaling, involve primary cilia that amplify tunable signals by ciliary length. This study tests ANKMY2, a protein regulating maturation and ciliary localization of membrane adenylyl cyclases. Kidney-specific ANKMY2 loss suppresses early postnatal cystogenesis, extends survival, and reduces adult cyst burden. Mechanistically, ANKMY2 controls trafficking of adenylyl cyclases without disrupting cilia, and ciliary elongation during both initial and progressive phases is ANKMY2-dependent.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages28

Reading Time1 h 11 min

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Abstract

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OPEN ACCESS Citation: Hwang S-H, Choi K, Badgandi H, White KA, Xun Y, Woodward OM, et al.(2025) Lack of ANKMY2 suppresses kidney cystogenesis in embryonic-and adult-onset polycystic kidney disease. PLoS Genet 21(12): e1012008. [https://doi.org/10.1371/journal](https://doi.org/10.1371/journal). pgen.1012008 Editor: Gregory J. Pazour, University of Massachusetts Chan Medical School, UNITED STATES OF AMERICA Received: September 11, 2025 Accepted: December 21, 2025 Published: December 31, 2025 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: [https://doi.org/10.1371/journal](https://doi.org/10.1371/journal). pgen.1012008 Copyright: © 2025 Hwang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, RESEARCH ARTICLE Lack of ANKMY2 suppresses kidney cystogenesis in embryonic-and adult-onset polycystic kidney disease Sun-Hee Hwang1, Kyungsuk Choi1, Hemant Badgandi1¤, Kevin A. White1, Yu Xun1, Owen M. Woodward2, Feng Qian3, Saikat Mukhopadhyay1* 1 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America, 2 Departments of Physiology and Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America, 3 Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America ¤ Present address: Department of Biology and Environmental Science, University of New Haven, West Haven, Connecticut, United States of America. * [saikat.mukhopadhyay@utsouthwestern.edu](saikat.mukhopadhyay@utsouthwestern.edu) Abstract Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive bilateral cyst formation. Multiple cellular pathways including second messenger cAMP signaling are dysregulated in ADPKD, but mechanisms initiating cysts are unknown. ADPKD is caused by mutations in PKD1/PKD2 genes encoding for polycystins that localize to primary cilia—nonmotile, microtubule-based dynamic compartments sensing extracellular chemical/mechanical signals. The compact cylindrical structure of cilia enables tunable signaling amplification regulatable by ciliary length. Severe cystogenesis from polycystin loss is cilia dependent and ciliary elongation is common in cystic epithelia. However, uncoupling the cilium-specific signals repressed by polycystins from downstream cystogenic pathways has proven challenging. Here we aim to understand roles of compartmentalized cAMP signaling in cystogenesis and ciliary length control. We investigated ANKMY2, an Ankyrin repeat MYND domain protein involved in maturation and ciliary localization of membrane adenylyl cyclases—enzymes generating cAMP. In kidney-specific Ankmy2/ Pkd1 knockout mice, loss of ANKMY2 suppressed early postnatal cystogenesis and significantly extended survival in an embryonic-onset Pkd1 deletion model. Similarly, in an adult inducible Pkd1 knockout model, ANKMY2 deficiency reduced cyst burden. Mechanistically, ANKMY2 controlled the ciliary trafficking of multiple adenylyl cyclases in mouse and human kidney epithelial cells without disrupting cilia while retaining cellular pools. Ciliary elongation began in dilatated tubules of adult onset ADPKD mice and further increased in cystic kidneys. Both initial and progressive phases of cilia lengthening were ANKMY2-dependent. Our findings indicate that ciliary adenylyl cyclase signaling likely promotes cilia-dependent cyst initiation distinct PLOS Genetics | [https://doi.org/10.1371/journal.pgen.1012008](https://doi.org/10.1371/journal.pgen.1012008) December 31, 2025 1 / 28 which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and sour

FAQs

What role does ANKMY2 play in ADPKD cyst formation?

ANKMY2 regulates maturation and ciliary localization of membrane adenylyl cyclases, and its loss suppresses cystogenesis in both embryonic-onset and adult-onset Pkd1 knockout models.

How does ANKMY2 affect cilia without disrupting them?

ANKMY2 deficiency controls ciliary trafficking of multiple adenylyl cyclases while retaining cellular pools and not disrupting cilia structure.

What is the relationship between ANKMY2 and ciliary lengthening during disease progression?

Both initial and progressive cilia lengthening during ADPKD are ANKMY2-dependent; kidneys lacking ANKMY2 do not show ciliary elongation despite elevated cAMP.

Sep 29, 2026

Upload by dhado