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Priv-Doz. Dr. med. Sandra Habbig
Children´s and Adolescents´ Hospital
University Hospital Cologne, Kerpener Str. 62
50937 Cologne, Germany
+49 221 478-4319
sandra.habbig@uk-koeln.de

Group Leader
Prof. Dr. med. Bernhard Schermer
Department II of Internal Medicine
University Hospital Cologne CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne, Germany
+49 221 478-89030
bernhard.schermer@uk-koeln.de

Institution
University Hospital of Cologne
Nephrolab Cologne
CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne, Germany

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Sandra Habbig, Bernhard Schermer

Transcriptional programs governed by YAP and TAZ and their nuclear control mechanisms in FSGS

The transcriptional regulators YAP and TAZ, downstream targets of Hippo signaling, are central for the homeostasis and survival of podocytes and as such indispensable to maintaining glomerular architecture and function. Remarkably, both hyperactivity YAP and TAZ, as well as loss of YAP and TAZ activity, are associated with podocyte damage and glomerular disease, and tightly controlled regulatory mechanisms are required to keep YAP and TAZ activity in balance. Fundamental studies revealed that YAP and TAZ act downstream of various pathways and biological processes receiving a plethora of inputs. While there appears to be a huge diversity of tissue and cell-specific mechanisms and functions to keep YAP/TAZ at check or to unleash their transcriptional functions, this converges in the nuclear shuttling of YAP and TAZ, their binding to transcription factors, the association with enhancer elements and their regulation through posttranslational modifications.

The overarching aim of our project is to uncover the nuclear functions and mechanisms of how YAP and TAZ activate overlapping and distinct transcriptional programs specifically in podocytes that can either promote injury or support survival. Specifically, we will investigate interchangeable and unique functions of YAP and TAZ and their effects on transcriptional programs involved in FSGS, study the transcriptional machinery orchestrated by YAP and TAZ and how nucleoporins regulate the dynamics of YAP/TAZ nuclear shuttling in podocytes and analyze the role of YAP and TAZ signaling in response to changes in glomerular hemodynamics. With this, we aim to discover novel ways to rewire podocytes’ YAP and/or TAZ signaling and to pave the way for novel therapeutic strategies for FSGS.

PROJECT RELATED PUBLICATIONS

Fabretti, F., Tschernoster, N., Erger, F., Hedergott, A., Buescher, A.K., Dafinger, C., Reusch, B., Kontges, V.K., Kohl, S., Bartram, M.P., Weber, L.T., Thiele, H., Altmueller, J., Schermer, B., Beck, B.B., and Habbig, S. (2021) Expanding the Spectrum of FAT1 Nephropathies by Novel Mutations That Affect Hippo Signaling. Kidney Int Rep,  6(5): 1368-1378.

Muller, R.U. and Schermer, B. (2020) Hippo signaling-a central player in cystic kidney disease? Pediatr Nephrol,  35(7): 1143-1152.

Butt, L., Unnersjo-Jess, D., Hohne, M., Edwards, A., Binz-Lotter, J., Reilly, D., Hahnfeldt, R., Ziegler, V., Fremter, K., Rinschen, M.M., Helmstadter, M., Ebert, L.K., Castrop, H., Hackl, M.J., Walz, G., Brinkkoetter, P.T., Liebau, M.C., Tory, K., Hoyer, P.F., Beck, B.B., Brismar, H., Blom, H., Schermer, B., and Benzing, T. (2020) A molecular mechanism explaining albuminuria in kidney disease. Nat Metab,  2(5): 461-474.

Rinschen, M.M., Grahammer, F., Hoppe, A.K., Kohli, P., Hagmann, H., Kretz, O., Bertsch, S., Hohne, M., Gobel, H., Bartram, M.P., Gandhirajan, R.K., Kruger, M., Brinkkoetter, P.T., Huber, T.B., Kann, M., Wickstrom, S.A., Benzing, T., and Schermer, B. (2017) YAP-mediated mechanotransduction determines the podocyte's response to damage. Sci Signal,  10(474).

Kohli, P., Bartram, M.P., Habbig, S., Pahmeyer, C., Lamkemeyer, T., Benzing, T., Schermer, B., and Rinschen, M.M. (2014) Label-free quantitative proteomic analysis of the YAP/TAZ interactome. Am J Physiol Cell Physiol,  306(9): C805-18.

Habbig, S., Bartram, M.P., Sagmuller, J.G., Griessmann, A., Franke, M., Muller, R.U., Schwarz, R., Hoehne, M., Bergmann, C., Tessmer, C., Reinhardt, H.C., Burst, V., Benzing, T., and Schermer, B. (2012) The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ. Hum Mol Genet,  21(26): 5528-38.

Habbig, S., Bartram, M.P., Muller, R.U., Schwarz, R., Andriopoulos, N., Chen, S., Sagmuller, J.G., Hoehne, M., Burst, V., Liebau, M.C., Reinhardt, H.C., Benzing, T., and Schermer, B. (2011) NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway. J Cell Biol,  193(4): 633-42.