Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation

Authors

Anthony J. Covarrubias, Harvard T.H. Chan School of Public Health
Halil Ibrahim Aksoylar, Harvard T.H. Chan School of Public Health
Jiujiu Yu, Harvard T.H. Chan School of Public HealthFollow
Nathaniel W. Snyder, University of Pennsylvania & Drexel University
Andrew J. Worth, University of Pennsylvania, Philadelphia
Shankar S. Iyer, Brigham and Women’s Hospital
Jiawei Wang, Chinese Academy of Sciences
Issam Ben-Sahra, Harvard T.H. Chan School of Public Health
Vanessa Byles, Harvard T.H. Chan School of Public Health
Tiffany Polynne-Stapornkul, Harvard T.H. Chan School of Public Health
Erika C. Espinosa, Harvard T.H. Chan School of Public Health
Dudley Lamming, University of Wisconsin-Madison
Brendan D. Manning, Harvard T.H. Chan School of Public Health
Yijing Zhang, Chinese Academy of Sciences
Ian A. Blair, University of Pennsylvania, Philadelphia
Tiffany Horng, Harvard T.H. ChanSchool of Public Health,Follow

Document Type

Article

Date of this Version

2-19-2016

Citation

Copyright Covarrubias et al.

Comments

Covarrubias et al. eLife 2016;5:e11612. DOI: 10.7554/eLife.11612 1 of 19

Abstract

Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation.