Vasohibins encode tubulin detyrosinating activity

Tubulin is subjected to a number of posttranslational modifications to generate heterogeneous microtubules. The modifications include removal and ligation of the carboxy-terminal tyrosine of ⍺-tubulin. Whereas enzymes for most modifications have been assigned, the enzymes responsible for detyrosination, an activity observed forty years ago, have remained elusive. We applied a haploid genetic screen to find regulators of tubulin detyrosination. We identified SVBP, a peptide that regulates the abundance of Vasohibins (VASH1 and VASH2). Vasohibins, but not SVBP alone, increased detyrosination of ⍺-tubulin and purified Vasohibins removed the carboxy-terminal tyrosine of ⍺-tubulin. Vasohibins played a cell-type dependent role in detyrosination, but cells also contain an additional detyrosinating activity. Thus Vasohibins, hitherto studied as secreted angiogenesis regulators, constitute a long-sought missing link in the tubulin tyrosination cycle.