Tulp3 Regulates Renal Cystogenesis by Trafficking of Cystoproteins to Cilia

Sun Hee Hwang, Bandarigoda N. Somatilaka, Hemant Badgandi, Vivek Reddy Palicharla, Rebecca Walker, John M. Shelton, Feng Qian, Saikat Mukhopadhyay

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Polycystic kidney disease proteins, polycystin-1 and polycystin-2, localize to primary cilia. Polycystin knockouts have severe cystogenesis compared to ciliary disruption, whereas simultaneous ciliary loss suppresses excessive cyst growth. These data suggest the presence of a cystogenic activator that is inhibited by polycystins and an independent but relatively minor cystogenic inhibitor, either of which are cilia dependent. However, current genetic models targeting cilia completely ablate the compartment, making it difficult to uncouple cystoprotein function from ciliary localization. Thus, the role of cilium-generated signaling in cystogenesis is unclear. We recently demonstrated that the tubby family protein Tulp3 determines ciliary trafficking of polycystins in kidney collecting duct cells without affecting protein levels or cilia. Here, we demonstrate that embryonic-stage, nephron-specific Tulp3 knockout mice developed cystic kidneys, while retaining intact cilia. Cystic kidneys showed increased mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), mTOR, and persistently high cyclic AMP (cAMP) signaling, suggesting contribution of multiple factors to cystogenesis. Based on kidney-to-body-weight ratio, cystic index, and epithelial proliferation in developing tubules or cysts, the severity of cystogenesis upon Tulp3 deletion was intermediate between that caused by loss of polycystin-1 or cilia. However, concomitant Tulp3 loss did not inhibit cystogenesis in polycystin-1 knockouts, unlike ciliary disruption. Interestingly, ciliary trafficking of the small guanosine triphosphatase (GTPase) Arl13b, loss of which causes cystogenic severity similar to ciliary loss, was reduced prior to cyst initiation. Thus, we propose that cystogenesis in Tulp3 mutants results from a reduction of ciliary levels of polycystins, Arl13b, and Arl13b-dependent lipidated cargoes. Arl13b might be the ciliary factor that represses cystogenesis distinct from polycystins. Hwang et al. show that embryonic-stage, nephron-specific Tulp3 knockouts develop cystic kidneys, while retaining intact cilia. The severity of cystogenesis is intermediate between that caused by loss of polycystin-1 or cilia. They uncover evidence that cystogenesis results from a reduction of ciliary levels of polycystins and the small GTPase Arl13b.

Original languageEnglish (US)
Pages (from-to)790-802.e5
JournalCurrent Biology
Volume29
Issue number5
DOIs
StatePublished - Mar 4 2019

Fingerprint

TRPP Cation Channels
Cilia
cilia
kidneys
Kidney
Cystic Kidney Diseases
Guanosine
Cysts
Nephrons
nephrons
Proteins
guanosinetriphosphatase
Extracellular Signal-Regulated MAP Kinases
mitogen-activated protein kinase
Collecting Kidney Tubules
Mitogen-Activated Protein Kinases
Cyclic AMP
Ducts
polycystins
Polycystic Kidney Diseases

Keywords

  • Arl13b
  • cAMP
  • cilia
  • cystogenesis
  • GTPase
  • Inpp5e
  • polycystic kidney disease
  • polycystin
  • tubby family protein
  • Tulp3

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Hwang, S. H., Somatilaka, B. N., Badgandi, H., Palicharla, V. R., Walker, R., Shelton, J. M., ... Mukhopadhyay, S. (2019). Tulp3 Regulates Renal Cystogenesis by Trafficking of Cystoproteins to Cilia. Current Biology, 29(5), 790-802.e5. https://doi.org/10.1016/j.cub.2019.01.047

Tulp3 Regulates Renal Cystogenesis by Trafficking of Cystoproteins to Cilia. / Hwang, Sun Hee; Somatilaka, Bandarigoda N.; Badgandi, Hemant; Palicharla, Vivek Reddy; Walker, Rebecca; Shelton, John M.; Qian, Feng; Mukhopadhyay, Saikat.

In: Current Biology, Vol. 29, No. 5, 04.03.2019, p. 790-802.e5.

Research output: Contribution to journalArticle

Hwang, SH, Somatilaka, BN, Badgandi, H, Palicharla, VR, Walker, R, Shelton, JM, Qian, F & Mukhopadhyay, S 2019, 'Tulp3 Regulates Renal Cystogenesis by Trafficking of Cystoproteins to Cilia', Current Biology, vol. 29, no. 5, pp. 790-802.e5. https://doi.org/10.1016/j.cub.2019.01.047
Hwang SH, Somatilaka BN, Badgandi H, Palicharla VR, Walker R, Shelton JM et al. Tulp3 Regulates Renal Cystogenesis by Trafficking of Cystoproteins to Cilia. Current Biology. 2019 Mar 4;29(5):790-802.e5. https://doi.org/10.1016/j.cub.2019.01.047
Hwang, Sun Hee ; Somatilaka, Bandarigoda N. ; Badgandi, Hemant ; Palicharla, Vivek Reddy ; Walker, Rebecca ; Shelton, John M. ; Qian, Feng ; Mukhopadhyay, Saikat. / Tulp3 Regulates Renal Cystogenesis by Trafficking of Cystoproteins to Cilia. In: Current Biology. 2019 ; Vol. 29, No. 5. pp. 790-802.e5.
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