Regulation of microtubule dynamics and functions

Carsten Janke

Carsten Janke Team Leader Tel:

Microtubules are key cytoskeletal elements involved in a large number of functions in eukaryotic cells.

They assemble from a protein dimer of a- and b-tubulin, two highly similar and conserved proteins. Tubulins are subject to a large variety of posttranslational modifications (Fig. 1), which provide a rapid and reversible mechanism to diversify microtubule functions in cells. Our team is studying the mechanisms and functional roles of these modifications by using an interdisciplinary approach.

Figure 1 : Représentation schématique des modifications post traductionnelles de la tubuline Ce schéma représente les trois modifications post traductionnelles qui affectent directement la queue C-terminale de la tubuline, ainsi que leurs mécanismes et les enzymes impliquées. Polyglutamylation et polyglycylation ont lieu sur les tubulines et , alors que la détyrosination est limitée à la tubuline .
Figure 1: Schematic representation of tubulin post-translational modifications The three modifications that directly modify the C-terminal tail of tubulin, their mechanisms and enzymes involved in the modifications are depicted. Polyglutamylation and polyglycylation take place on both, α- and β-tubulin, whereas detyrosination is restricted to α-tubulin.

Our team has identified the enzymes involved in the posttranslational polyglutamylation (1, 2), deglutamylation (3, 4) and polyglycylation (5) of tubulin. Following the discovery of these enzymes, we are now investigating (i) the molecular mechanisms, and (ii) the biological functions of tubulin-modifying enzymes.

Polyglutamylation and polyglycylation take place within the C-terminal tails of the tubulin molecules. These tails are localized at the outer surface of the microtubule (Fig. 1), thus their posttranslational modification is most likely regulating the interactions of microtubules with their multiple binding partners, commonly known as microtubule-associated proteins (MAPs) and molecular motors. So far we have demonstrated that the microtubule-severing protein spastin is regulated by tubulin polyglutamylation (6), and that tubulin glycylation stabilizes ciliary axonemes by a yet unknown molecular mechanism (5, 7). Our functional studies have demonstrated an important role for both, polyglutamylation and polyglycylation for motile and primary cilia in mammals (7, 8), and we have found that polyglutamylation is directly linked to neurodegeneration in mice (4). We have further demonstrated a direct link between altered levels of a tubulin glycylase and colorectal cancer development (8).

In our ongoing projects, we are using biochemistry, biophysics and structural biology in conjunction with cell and mouse biology to identify the molecular mechanisms by which tubulin posttranslational modifications regulative microtubule behaviour and functions, and which are the cellular and developmental roles of these modifications and the corresponding enzymes. Our functional studies are focussed on the nervous system, cilia and flagella (including spermatogenesis), and cell division. Our team is closely collaborating with clinicians to delineate the implications of tubulin posttranlsational modifications in human pathologies.

Our recent discoveries

Key publications

Year of publication 2018

Maria M Magiera, Satish Bodakuntla, Jakub Žiak, Sabrina Lacomme, Patricia Marques Sousa, Sophie Leboucher, Torben J Hausrat, Christophe Bosc, Annie Andrieux, Matthias Kneussel, Marc Landry, André Calas, Martin Balastik, Carsten Janke (2018 Nov 12)

Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport.

The EMBO journal. : DOI : e100440
Vandana Shashi, Maria M Magiera, Dennis Klein, Maha Zaki, Kelly Schoch, Sabine Rudnik-Schöneborn, Andrew Norman, Osorio Lopes Abath Neto, Marina Dusl, Xidi Yuan, Luca Bartesaghi, Patrizia De Marco, Ahmed A Alfares, Ronit Marom, Stefan T Arold, Francisco J Guzmán-Vega, Loren Dm Pena, Edward C Smith, Maja Steinlin, Mohamed Oe Babiker, Payam Mohassel, A Reghan Foley, Sandra Donkervoort, Rupleen Kaur, Partha S Ghosh, Valentina Stanley, Damir Musaev, Caroline Nava, Cyril Mignot, Boris Keren, Marcello Scala, Elisa Tassano, Paolo Picco, Paola Doneda, Chiara Fiorillo, Mahmoud Y Issa, Ali Alassiri, Ahmed Alahmad, Amanda Gerard, Pengfei Liu, Yaping Yang, Birgit Ertl-Wagner, Peter G Kranz, Ingrid M Wentzensen, Rolf Stucka, Nicholas Stong, Andrew S Allen, David B Goldstein, , Benedikt Schoser, Kai M Rösler, Majid Alfadhel, Valeria Capra, Roman Chrast, Tim M Strom, Erik-Jan Kamsteeg, Carsten G Bönnemann, Joseph G Gleeson, Rudolf Martini, Carsten Janke, Jan Senderek (2018 Nov 12)

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

The EMBO journal. : DOI : e100540
Maria M Magiera, Puja Singh, Carsten Janke (2018 May 31)

SnapShot: Functions of Tubulin Posttranslational Modifications.

Cell : 1552-1552.e1 : DOI : 10.1016/j.cell.2018.05.032
Maria M Magiera, Puja Singh, Sudarshan Gadadhar, Carsten Janke (2018 May 31)

Tubulin Posttranslational Modifications and Emerging Links to Human Disease.

Cell : 1323-1327 : DOI : 10.1016/j.cell.2018.05.018
Renaud Chabrier, Carsten Janke (2018 Mar 1)

The comeback of hand drawing in modern life sciences.

Nature reviews. Molecular cell biology : DOI : 10.1038/nrm.2017.126

Year of publication 2017

Sudarshan Gadadhar, Hala Dadi, Satish Bodakuntla, Anne Schnitzler, Ivan Bièche, Filippo Rusconi, Carsten Janke (2017 Sep 4)

Tubulin glycylation controls primary cilia length.

The Journal of cell biology : 2701-2713 : DOI : 10.1083/jcb.201612050
All publications