Reactive Oxygen Species, AMP-activated Protein Kinase, and the Transcription Cofactor p300 Regulate α-Tubulin Acetyltransferase-1 (αTAT-1/MEC-17)-dependent Microtubule Hyperacetylation during Cell Stress

Rafah Mackeh; Séverine Lorin; Ameetha Ratier; Najet Mejdoubi-Charef; Anita Baillet; Arnaud Bruneel; Ahmed Hamaï; Patrice Codogno; Christian Poüs; Daniel Perdiz

doi:10.1074/jbc.M113.507400

Reactive Oxygen Species, AMP-activated Protein Kinase, and the Transcription Cofactor p300 Regulate α-Tubulin Acetyltransferase-1 (αTAT-1/MEC-17)-dependent Microtubule Hyperacetylation during Cell Stress*

From the ^‡Université Paris Sud, EA4530, Faculté de Pharmacie, Châtenay-Malabry, France,
^§Assistance Publique-Hôpitaux de Paris, Service de Biochimie Métabolique et Cellulaire, Hôpital Bichat, 75018 Paris, France,
^¶INSERM U845, Université Paris Descartes, 75014 Paris, France, and
the ^‖Biochimie-Hormonologie, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, 92141 Clamart, France

↵1 To whom correspondence should be addressed: EA4530, Université Paris-Sud, UFR de Pharmacie, 5 Rue J. B. Clément, 92296 Châtenay-Malabry, France. Tel.: 33-146835477; E-mail: christian.pous{at}u-psud.fr.

Background: Tubulin acetylation is a hallmark of microtubule stabilization, which may modulate the binding of microtubule-associated proteins.

Results: Microtubules are hyperacetylated because of stress-induced cellular signaling upstream of the tubulin acetyltransferase MEC-17/αTAT1.

Conclusion: MEC-17/αTAT1 is regulated by p300, reactive oxygen species, and AMP-activated protein kinase.

Significance: Microtubule hyperacetylation is important for cell adaptation to stress through autophagy induction and for cell survival.

Abstract

Beyond its presence in stable microtubules, tubulin acetylation can be boosted after UV exposure or after nutrient deprivation, but the mechanisms of microtubule hyperacetylation are still unknown. In this study, we show that this hyperacetylation is a common response to several cellular stresses that involves the stimulation of the major tubulin acetyltransferase MEC-17. We also demonstrate that the acetyltransferase p300 negatively regulates MEC-17 expression and is sequestered on microtubules upon stress. We further show that reactive oxygen species of mitochondrial origin are required for microtubule hyperacetylation by activating the AMP kinase, which in turn mediates MEC-17 phosphorylation upon stress. Finally, we show that preventing microtubule hyperacetylation by knocking down MEC-17 affects cell survival under stress conditions and starvation-induced autophagy, thereby pointing out the importance of this rapid modification as a broad cell response to stress.