Post-translational polymodification of β1-tubulin regulates motor protein localization in platelet production and function
Abdullah O. Khan,
Alexandre Slater,
Annabel Maclachlan,
Phillip L.R. Nicolson,
Jeremy A. Pike,
Jasmeet S. Reyat,
Jack Yule,
Rachel Stapley,
Julie Rayes,
Steven G. Thomas,
Neil V. Morgan
Affiliations
Abdullah O. Khan
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT
Alexandre Slater
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT
Annabel Maclachlan
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT
Phillip L.R. Nicolson
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT
Jeremy A. Pike
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT; Centre of Membrane and Protein and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands
Jasmeet S. Reyat
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT
Jack Yule
Centre of Membrane and Protein and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands
Rachel Stapley
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT
Julie Rayes
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT
Steven G. Thomas
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT; Centre of Membrane and Protein and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands
Neil V. Morgan
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT
In specialized cells, the expression of specific tubulin isoforms and their subsequent post-translational modifications drive and coordinate unique morphologies and behaviors. The mechanisms by which β1-tubulin, the platelet and megakaryocyte (MK) lineage restricted tubulin isoform, drives platelet production and function remains poorly understood. We investigated the roles of two key post-translational tubulin polymodifications (polyglutamylation and polyglycylation) on these processes using a cohort of thrombocytopenic patients, human induced pluripotent stem cell derived MK, and healthy human donor platelets. We find distinct patterns of polymodification in MK and platelets, mediated by the antagonistic activities of the cell specific expression of tubulin tyrosine ligase like enzymes and cytosolic carboxypeptidase enzymes. The resulting microtubule patterning spatially regulates motor proteins to drive proplatelet formation in megakaryocytes, and the cytoskeletal reorganization required for thrombus formation. This work is the first to show a reversible system of polymodification by which different cell specific functions are achieved.
