A role for tubulin in cellular quality control and proteostasis

Abstract

Microtubules, stiff rods built up from tubulin dimers, form a cytoskeletal network whose structure, behaviour, and function have been extensively investigated, mainly from a mechanical perspective. Here, we describe a role for tubulin in the cellular stress response. We overexpressed tubulin dimers in a controlled fashion in 293F cells. Despite the engagement of autoregulation, a mechanism that degrades tubulin-encoding mRNAs when tubulin levels are high, a surplus of tubulin and microtubules is detected in overexpressing cells. This leads to altered microtubule behaviour, mitotic problems, deregulation of the cell cycle, and replication stress. Surprisingly, we also observe proteostasis defects in tubulin overexpressing cells, which we attribute to mitochondrial stress-related translation attenuation. Conversely, tubulin and microtubules are downregulated as part of the response to oxygen or glutamine deprivation. Together, our data link tubulin levels, and hence autoregulation, to cellular quality control and proteostasis. We propose that competitive interactions with key partners, including the mitochondrial protein import and general translation machinery, underlie the tubulin-mediated control of cellular homeostasis.