The role of transcriptional ‘futile cycles’ in autophagy and microbial pathogenesis

Authors:

Guowu Hu1, Travis McQuiston1, Amélie Bernard2, Yoon-Dong Park1, Jin Qiu1, Ali Vural3, Nannan Zhang1, Scott R. Waterman1, Nathan H. Blewett4, Timothy G. Myers5, John H. Kehrl3, Gulbu Uzel1, Daniel J. Klionsky2 and Peter R. Williamson1

doi: 10.15698/mic2015.08.221
Volume 2, pp. 302 to 304, published 30/07/2015.

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Affiliations:

1 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.

2 Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA 48109.

3 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.

4 Intramural Research Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.

5 Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA, 20892.

Keywords: 

autoimmunity, autophagy, fungus, pathogen, phosphorylation, TOR, translation, virulence

Corresponding Author(s):

Peter Williamson, Bld 10, Rm 11N222, 9000 Rockville Pike; Bethesda, MD, 20892, USA williamsonpr@mail.nih.gov

Conflict of interest statement:

No potential conflicts of interest were disclosed.

Please cite this article as:

Guowu Hu, Travis McQuiston, Amélie Bernard, Yoon-Dong Park, Jin Qiu, Ali Vural, Nannan Zhang, Scott R. Waterman, Nathan H. Blewett4, Timothy G. Myers5, John H. Kehrl3, Gulbu Uzel1, Daniel J. Klionsky and Peter R. Williamson (2015). The role of transcriptional ‘futile cycles’ in autophagy and microbial pathogenesis. Microbial Cell 2(8): 302-304.

© 2015 Hu et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

Eukaryotic cells utilize macroautophagy (hereafter autophagy) to recycle cellular materials during nutrient stress. Target of rapamycin (Tor) is a central regulator of this process, acting by post-translational mechanisms, phosphorylating preformed autophagy-related (Atg) proteins to repress autophagy during log-phase growth. We recently reported an additional role for post-transcriptional regulation of autophagy, whereby the mRNA decapping protein, Dcp2, undergoes Tor-dependent phosphorylation, resulting in increased ATG mRNA decapping and degradation under nutrient-rich, repressing conditions. Dephosphorylation of Dcp2 during starvation is associated with dissociation of the decapping-ATG mRNA complex, with resultant stabilization of, and accumulation of, ATG transcripts, leading to induction of autophagy. Regulation of mRNA degradation occurs in concert with known mRNA synthetic inductive mechanisms to potentiate overall transcriptional regulation. This mRNA degradative pathway thus constitutes a type of transcriptional ‘futile cycle’ where under nutrient-rich conditions transcript is constantly being generated and degraded. As nutrient levels decline, steady state mRNA levels are increased by both inhibition of degradation as well as increased de novo synthesis. A role for this regulatory process in fungal virulence was further demonstrated by showing that overexpression of the Dcp2-associated mRNA-binding protein Vad1 in the AIDS-associated pathogen Cryptococcus neoformans results in constitutive repression of autophagy even under starvation conditions as well as attenuated virulence in a mouse model. In summary, Tor-dependent post-transcriptional regulation of autophagy plays a key role in the facilitation of microbial pathogenesis.