Project A01

Project leaders: Michael Boutros and Irmgard Sinning

Mechanisms of Wnt protein secretion

Wnt proteins are lipidated glycoproteins which require a specialized secretion machinery for their export. Previously, we identified in genetic screens the Wnt cargo-receptor Evi/Wls as an essential factor for Wnt secretion and studied its role ex vivo and in vivo. Nevertheless, it remains currently unclear how Evi/Wls interacts on a molecular level with different proteins in the secretion and ERAD pathways in order to regulate the secretion of Wnt ligands. To address these questions, we will identify novel Wnt secretion components by a genetic screen in Drosophila, analyze the biochemical interactions and the structure of Evi/Wls with interacting proteins and will further characterize the functions of novel regulators.

 

Mechanismen der Sekretion von Wnt-Proteinen

Wnt-Liganden sind Lipid-modifizierte Glykoproteine, die einen spezialisierten Transportmechanismus für die Sekretion aus Zellen verwenden. Wir haben über genetische Screens den Wnt Cargo-Rezeptor Evi/Wls als essentiellen Faktor für die Wnt-Sekretion identifiziert und dessen Rolle in vivo und ex vivo analysiert. Ungeklärt bleibt, wie Evi/Wls mit anderen Proteinen des Sekretionswegs interagiert, um Wnt-Proteine zu sekretieren. Um dieser Frage nachzugehen, werden wir neue Komponenten für die Wnt-Sekretion durch genetische Screens in Drosophila identifizieren und charakterisieren sowie die biochemischen Interaktionen und die Struktur von Evi/Wls mit verschiedenen Interaktionspartnern analysieren.

Project-related publications

  • McDowell, M.A., M. Heimes, F. Fiorentino, S. Mehmood, Á. Farkas, J. Coy-Vergara, D. Wu, J.R. Bolla, V. Schmid, R. Heinze, K. Wild, D. Flemming, S. Pfeffer, B. Schwappach, C.V. Robinson, and I. Sinning. 2020. Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex. Mol Cell. 80:72-86.e77. PMID: 32910895
  • Port, F., C. Strein, M. Stricker, B. Rauscher, F. Heigwer, J. Zhou, C. Beyersdorffer, J. Frei, A. Hess, K. Kern, L. Lange, N. Langner, R. Malamud, B. Pavlovic, K. Radecke, L. Schmitt, L. Voos, E. Valentini, and M. Boutros. 2020. A large-scale resource for tissue-specific CRISPR mutagenesis in Drosophila. Elife. 9. PMID: 32053108
  • Wild, K., M. Aleksić, K. Lapouge, K.D. Juaire, D. Flemming, S. Pfeffer, and I. Sinning. 2020. MetAP-like Ebp1 occupies the human ribosomal tunnel exit and recruits flexible rRNA expansion segments. Nat Commun. 11:776. PMID: 32034140
  • Zhang, Y., G. Valentín Gesé, C. Conz, K. Lapouge, J. Kopp, T. Wölfle, S. Rospert, and I. Sinning. 2020. The ribosome-associated complex RAC serves in a relay that directs nascent chains to Ssb. Nat Commun. 11:1504. PMID: 32198371.
  • Chaudhary, V., and M. Boutros. 2019. Exocyst-mediated apical Wg secretion activates signaling in the Drosophila wing epithelium. PLoS Genet. 15:e1008351. PMID: 31527874
  • Chaudhary, V., S. Hingole, J. Frei, F. Port, D. Strutt, and M. Boutros. 2019. Robust Wnt signaling is maintained by a Wg protein gradient and Fz2 receptor activity in the developing Drosophila wing. Development. 146. PMID: 31399474
  • Glaeser, K., M. Urban, E. Fenech, O. Voloshanenko, D. Kranz, F. Lari, J.C. Christianson, and M. Boutros. 2018. ERAD-dependent control of the Wnt secretory factor Evi. EMBO J. 37. PMID: 29378775
  • Weyer, F.A., A. Gumiero, G.V. Gesé, K. Lapouge, and I. Sinning. 2017. Structural insights into a unique Hsp70-Hsp40 interaction in the eukaryotic ribosome-associated complex. Nat Struct Mol Biol. 24:144-151. PMID: 28067917.
  • Stefer, S., S. Reitz, F. Wang, K. Wild, Y.Y. Pang, D. Schwarz, J. Bomke, C. Hein, F. Löhr, F. Bernhard, V. Denic, V. Dötsch, and I. Sinning. 2011. Structural basis for tail-anchored membrane protein biogenesis by the Get3-receptor complex. Science. 333:758-762. PMID: 21719644
  • Bartscherer, K., N. Pelte, D. Ingelfinger, and M. Boutros. 2006. Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell. 125:523-533. PMID:16678096