Die molekularen Funktionen von Nephrocytin-4
Zusammenfassung der Projektergebnisse
Nephronophthisis (NPH) is an autosomal recessive disease caused by more than 20 different gene mutations that is often associated with end-stage renal disease in children. Almost all NPH gene products (NPHPs) localize to the cilium, a microtubular structure with specialized signaling properties and important developmental functions. NPHPs seem to be particularly important to establish the transition zone, a compartment adjacent to the basal body that appears to function as a gate-keeper, regulating the access of proteins and lipids to the ciliary axoneme. Significant progress has been made to define a hierarchy of NPHPs that control the establishment and maintenance of the transition zone, using C. elegans as a model system. We exploited the multi-ciliated cells of the Xenopus epidermis to obtain insight into the molecular function of NPHPs. We observed that NPHP4, one of the key components of the NPHP protein networks, recruits the actin modifying protein Daam1 through interaction with Inturned. This interaction has important implications for the normal assembly of the subapical actin layer, a part of the apical actin cytoskeleton that seems to be particularly important for basal body docking and subsequent ciliogenesis. Ongoing studies and unpublished data extend this initial observation to the NPHP1-NPHP4 module, demonstrating that NPHP1 interacts with the actin nucleator Spire1, an interaction that is disrupted by NPHP4 and NPHP9. Since depletion of spire1 resembles the defects caused by nphp4 knockdown, future works needs to elucidate the dynamics between NPHP1, NPHP4, NPHP9 and Spire1.
Projektbezogene Publikationen (Auswahl)
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(2013). ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet 45, 951-956
Hoff, S., Halbritter, J., Epting, D., Frank, V., Nguyen, T.M., van Reeuwijk, J., Boehlke, C., Schell, C., Yasunaga, T., Helmstadter, M., Mergen, M., Filhol, E., Boldt, K., Horn, N., Ueffing, M., Otto, E.A., Eisenberger, T., Elting, M.W., van Wijk, J.A., Bockenhauer, D., Sebire, N.J., Rittig, S., Vyberg, M., Ring, T., Pohl, M., Pape, L., Neuhaus, T.J., Elshakhs, N.A., Koon, S.J., Harris, P.C., Grahammer, F., Huber, T.B., Kuehn, E.W., Kramer-Zucker, A., Bolz, H.J., Roepman, R., Saunier, S., Walz, G., Hildebrandt, F., Bergmann, C., and Lienkamp, S.S
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(2014). Interaction with the Bardet-Biedl gene product TRIM32/BBS11 modifies the half-life and localization of Glis2/NPHP7. J Biol Chem 289, 8390-8401
Ramachandran, H., Schafer, T., Kim, Y., Herfurth, K., Hoff, S., Lienkamp, S.S., Kramer-Zucker, A., and Walz, G.
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(2015). Anks3 interacts with nephronophthisis proteins and is required for normal renal development. Kidney Int 87, 1191-1200
Yakulov, T.A., Yasunaga, T., Ramachandran, H., Engel, C., Muller, B., Hoff, S., Dengjel, J., Lienkamp, S.S., and Walz, G.
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(2015). SUMOylation Blocks the Ubiquitin-Mediated Degradation of the Nephronophthisis Gene Product Glis2/NPHP7. PLoS One 10, e0130275
Ramachandran, H., Herfurth, K., Grosschedl, R., Schafer, T., and Walz, G.
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(2015). The polarity protein Inturned links NPHP4 to Daam1 to control the subapical actin network in multiciliated cells. J Cell Biol 211, 963-973
Yasunaga, T., Hoff, S., Schell, C., Helmstadter, M., Kretz, O., Kuechlin, S., Yakulov, T.A., Engel, C., Muller, B., Bensch, R., Ronneberger, O., Huber, T.B., Lienkamp, S.S., and Walz, G.
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(2016). FAT1 mutations cause a glomerulotubular nephropathy. Nat Commun 7, 10822
Gee, H.Y., Sadowski, C.E., Aggarwal, P.K., Porath, J.D., Yakulov, T.A., Schueler, M., Lovric, S., Ashraf, S., Braun, D.A., Halbritter, J., Fang, H., Airik, R., Vega- Warner, V., Cho, K.J., Chan, T.A., Morris, L.G., ffrench-Constant, C., Allen, N., McNeill, H., Buscher, R., Kyrieleis, H., Wallot, M., Gaspert, A., Kistler, T., Milford, D.V., Saleem, M.A., Keng, W.T., Alexander, S.I., Valentini, R.P., Licht, C., Teh, J.C., Bogdanovic, R., Koziell, A., Bierzynska, A., Soliman, N.A., Otto, E.A., Lifton, R.P., Holzman, L.B., Sibinga, N.E., Walz, G., Tufro, A., and Hildebrandt, F.
