Regulation of microtubule detyrosination by Ca2+ and conventional calpains

Abstract

Detyrosination is a major post-translational modification of microtubules (MTs), which has significant impact on MT function in cell division, differentiation, growth, migration, and intracellular trafficking. Detyrosination of α-tubulin occurs mostly via the recently identified complex of vasohibin1/2 (VASH1/2) and small vasohibin binding protein (SVBP). However, there is still remaining detyrosinating activity in the absence of VASH1/2:SVBP, and little is known about the regulation of detyrosination. Here, we found that intracellular calcium is required for efficient MT detyrosination. Furthermore, we show that calcium-dependent proteases calpains 1 and 2 regulate MT detyrosination in VASH1:SVBP overexpressing human embryonal kidney (HEK293T) cells. We identified new calpain cleavage sites in the N-terminal disordered region of VASH1. However, this cleavage did not affect the enzymatic activity of VASH. In conclusion, we suggest that the regulation of VASH1-mediated MT detyrosination by calpains could occur independent of VASH catalytic activity or via another yet unknown tubulin carboxypeptidase. Importantly, calpains’ calcium dependency could allow a fine regulation of MT detyrosination. Thus, identifying the calpain-regulated pathway of MT detyrosination can be of major importance for basic and clinical research.

Decoding microtubule detyrosination: enzyme families, structures, and functional implications

“…It is unclear whether combinations of tubulin modifications have antagonistic effects, or specialised roles on microtubule behaviour and function. Calcium signalling has also been implicated in detyrosination through calpains [50]. While the disordered N‐terminus of vasohibins has a calpain cleavage site, this does not seem to affect detyrosination [50].…”

“…Calcium signalling has also been implicated in detyrosination through calpains [50]. While the disordered N‐terminus of vasohibins has a calpain cleavage site, this does not seem to affect detyrosination [50].…”