Asymmetric requirement for α-tubulin over β-tubulin

Abstract

How cells regulate the supply of α- and β-tubulin monomers to meet the demand for αβ-heterodimers while avoiding consequences of monomer imbalance is not understood. We investigate the role of gene copy number in tubulin regulation and how shifting the expression of α- or β-tubulin genes impacts tubulin proteostasis and microtubule function. We find that α-tubulin gene copy number is important for maintaining an excess α-tubulin protein compared to β-tubulin protein and preventing accumulation of super-stoichiometric β-tubulin. Super-stoichiometric β-tubulin is toxic to cells, leading to loss of microtubules, formation of non-microtubule assemblies of tubulin, and disrupted cell proliferation. In contrast, decreased β-tubulin or increased α-tubulin has minor effects. We provide evidence that cells rapidly equilibrate the concentration of α-tubulin protein during shifts in α-tubulin isotype expression to maintain a ratio in excess of β-tubulin. We propose an asymmetric relationship between α- and β-tubulins, where α-tubulins are maintained in excess to supply αβ-heterodimers and limit the accumulation of β-tubulin monomers.

TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish

“…While we did observe changes in tubulin PTMs, we did not observe changes in microtubule polymerization. This could be due to the fact that expression of total α-tubulin was not affected by the reduction of tuba8l2 (Wethekam and Moore, 2022). Overall, these data support that, apart from ALS cases bearing a TUBA4A mutation, dysregulated TUBA4A expression plays an important role in sporadic ALS disease pathogenesis, and stresses the importance of microtubule dysfunction in ALS.…”