title: The role of transcriptional 'futile cycles' in autophagy and microbial pathogenesis.
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 increasedATGmRNA decapping and degradation under nutrient-rich, repressing conditions. Dephosphorylation of Dcp2 during starvation is associated with dissociation of the decapping-ATGmRNA complex, with resultant stabilization of, and accumulation of,ATGtranscripts, 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 increasedde novosynthesis. 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 pathogenCryptococcus neoformansresults 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.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Guowu
authors.initials: G
authors.lastname: Hu
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Travis
authors.initials: T
authors.lastname: McQuiston
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA 48109.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bernard
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Yoon-Dong
authors.initials: YD
authors.lastname: Park
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Jin
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Ali
authors.initials: A
authors.lastname: Vural
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Waterman
authors.affiliation: Intramural Research Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Nathan H
authors.initials: NH
authors.lastname: Blewett
authors.affiliation: Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA, 20892.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Myers
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: John H
authors.initials: JH
authors.lastname: Kehrl
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA 48109.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
keywords: TOR; autoimmunity; autophagy; fungus; pathogen; phosphorylation; translation; virulence