Post-translational polymodification of β1-tubulin regulates motor protein localisation in platelet production and function

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Abstract

In specialised cells, the expression of specific tubulin isoforms and their subsequent post-translational modifications drive and coordinate unique morphologies and behaviours. 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 (iPSC) derived MKs, and healthy human donor platelets. We find distinct patterns of polymodification in MKs and platelets, mediated by the antagonistic activities of the cell specific expression of Tubulin Tyrosine Ligase Like (TTLLs) and Cytosolic Carboxypeptidase (CCP) enzymes. The resulting microtubule patterning spatially regulates motor proteins to drive proplatelet formation in megakaryocytes, and the cytoskeletal reorganisation required for thrombus formation. This work is the first to show a reversible system of polymodification by which different cell specific functions are achieved.
Original languageEnglish
Pages (from-to)1-43
JournalHaematologica
Volume2020
Issue number00
Early online date17 Dec 2020
DOIs
Publication statusE-pub ahead of print - 17 Dec 2020

Bibliographical note

Acknowledgements: We thank the families for providing samples and our clinical and laboratory colleagues for their help. This work was supported by the British Heart Foundation (PG/13/36/30275; FS/13/70/30521; FS/15/18/31317; PG/16/103/32650;
IG/18/2/33544). The authors would like to thank the TechHub and COMPARE Core facilities at the University of Birmingham. AOK is a Wellcome funded Sir Henry Wellcome Fellow (218649/Z/19/Z). We thank Professor Steve Watson for his ongoing support and invaluable mentorship.

ASJC Scopus subject areas

  • Hematology

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