The molecular mechanisms and therapeutic targeting of microtubule glutamylation in mitosis and cancer.

Abstract

Microtubule glutamylation is a dynamic post-translational modification that involves the addition of glutamate chains to tubulin, a process crucial for reshaping the biochemical interface of microtubules. This modification orchestrates an array of vital cellular functions, including cell division, neuronal development, and ciliary biology. We first delineate the molecular machinery by which glutamylation governs successive stages of cell division, encompassing centrosome-driven spindle assembly, spindle pole integrity maintenance, and the coordination of late mitotic events for faithful chromosome segregation and cytokinesis. We then examine how the dysregulation of this system drives oncogenesis. This includes loss-of-function perturbations, such as the downregulation of the tumor-suppressive enzyme TTLL11, which promotes chromosomal instability, as well as gain-of-function events involving oncogenic glutamylases like TTLL4, TTLL6, and TTLL12, which reprogram cytoskeletal dynamics to fuel proliferation, metastasis, and therapy resistance. Finally, we evaluate the resulting therapeutic landscape, discussing evolving strategies from metabolic intervention and direct enzyme inhibition to cutting-edge modalities like targeted protein degradation and synthetic biology for precision correction. Our analysis positions the glutamylation pathway not only as a fundamental regulator of cell division but also as a promising and multifaceted target for novel cancer therapeutics.