Regulation of autophagy by stress-responsive transcription factors

Abstract

Autophagy is an evolutionarily conserved process that promotes the lysosomal degradation of intracellular components including organelles and portions of the cytoplasm. Besides operating as a quality control mechanism in steady-state conditions, autophagy is upregulated in response to a variety of homeostatic perturbations. In this setting, autophagy mediates prominent cytoprotective effects as it sustains energetic homeostasis and contributes to the removal of cytotoxic stimuli, thus orchestrating a cell-wide, multipronged adaptive response to stress. In line with the critical role of autophagy in health and disease, defects in the autophagic machinery as well as in autophagy-regulatory signaling pathways have been associated with multiple human pathologies, including neurodegenerative disorders, autoimmune conditions and cancer. Accumulating evidence indicates that the autophagic response to stress may proceed in two phases. Thus, a rapid increase in the autophagic flux, which occurs within minutes or hours of exposure to stressful conditions and is entirely mediated by post-translational protein modifications, is generally followed by a delayed and protracted autophagic response that relies on the activation of specific transcriptional programs. Stress-responsive transcription factors including p53, NF-κB and STAT3 have recently been shown to play a major role in the regulation of both these phases of the autophagic response. Here, we will discuss the molecular mechanisms whereby autophagy is orchestrated by stress-responsive transcription factors.

Keywords: AEN; AMP-activated protein kinase; AMPK; BCL2/adenovirus E1B 19kDa interacting protein 3; BECN1; BNIP3; Beclin 1; Cancer; DAPK1; DNA-damage regulated autophagy modulator 1; DRAM1; EGFR; EIF2AK3; FOXO; HIF-1; HSF1; IGFBP3; IKK; IκB; IκB kinase; JAK; Janus kinase; MAP1LC3; MAPK; MEF; Mitophagy; NF-κB-inducing kinase; NIK; NLS; PAMP; PI3K; PINK1; PKR; PTEN; PTEN-induced putative kinase 1; RB1-inducible coiled-coil protein 1; RB1CC1; REL homology domain; RHD; SQSTM1; STAT3; TAB; TAK1; TAK1-binding protein; TIGAR; TNF; TNF receptor 1; TNFR1; TP53-induced glycolysis and apoptosis regulator; TSC2; apoptosis enhancing nuclease; death-associated protein kinase 1; eIF2α; epidermal growth factor receptor; eukaryotic translation initiation factor 2α; eukaryotic translation initiation factor 2α kinase 3; forkhead box O; heat shock transcription factor 1; hypoxia-inducible factor 1; inhibitor of κB; insulin-like growth factor-binding protein 3; mTOR; mammalian target of rapamycin; microtubule-associated protein 1 light chain 3; mitogen-activated protein kinase; mouse embryonic fibroblast; nuclear localization signal; pathogen-associated molecular pattern; phosphatase and tensin homolog; phosphoinositide-3-kinase; protein kinase, RNA-activated; sequestosome 1; signal transducer and activator of transcription 3; transforming growth factor β-activated kinase 1; tuberous sclerosis 2; tumor necrosis factor.