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

Microbial Cell

Timothy G. Myers¹  Nathan H. Blewett²  Gulbu Uzel³  Travis McQuiston³  Yoon-Dong Park³  Peter R. Williamson³  Scott R. Waterman³  Guowu Hu³  Nannan Zhang³  Jin Qiu³  Ali Vural⁴  John H. Kehrl⁴  Daniel J. Klionsky⁵  Amélie Bernard⁵ 

[1] Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, USA, 20892.;Intramural Research Program in Genomics of Differentiation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.;Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA, 20892.;Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA 48109.;

关键词: autoimmunity;    autophagy;    fungus;    pathogen;    phosphorylation;    TOR;    translation;    virulence;   

DOI  :  10.15698/mic2015.08.221

来源: DOAJ

【 摘 要 】

Eukaryotic cells utilize macroautophagy (hereafter autophagy)torecyclecellular materialsduringnutrient stress. Target of rapamycin (Tor) is a central regulator ofthisprocess,actingbypost-translationalmechanisms,phosphorylatingpreformedautophagy-related (Atg) proteins to repress autophagy during log-phase growth.Werecentlyreportedanadditionalrolefor post-transcriptional regulation of autophagy, where by themRNAdecappingprotein,Dcp2,undergoesTor-dependent phosphorylation, resulting in increased ATG mRNA decapping and degradation under nutrient-rich, repressing conditions. Dephosphorylation of Dcp2 duringstarvationisassociatedwithdissociationofthe decapping-ATG mRNA complex, with resultant stabilization of, and accumulation of, ATG transcripts, leadingtoinductionofautophagy.RegulationofmRNA degradation occurs in concert with known mRNA syntheticinductivemechanismstopotentiateoverall transcriptionalregulation.ThismRNAdegradative pathway thus constitutes a type of transcriptional ‘futilecycle’whereundernutrient-richconditionstranscript 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 novosynthesis. A role for this regulatory process in fungal virulence was further demonstrated by showing that overexpression of the Dcp2-associated mRNA-bindingproteinVad1intheAIDS-associated pathogen Cryptococcus neoformansresults in constitutiverepressionofautophagyevenunderstarvation conditions as well as attenuated virulence in a mouse model. In summary, Tor-dependent post-transcriptionalregulationofautophagyplaysakeyrole in the facilitation of microbial pathogenesis.

【 授权许可】

Unknown