Abstract
Cellular adaptation to various types of stress requires a complex network of steps that altogether lead to reconstitution of redox balance, degradation of damaged macromolecules and restoration of cellular metabolism. Advances in our understanding of the interplay between cellular signalling and signal translation paint a complex picture of multi-layered paths of regulation. In this review we explore the link between cellular adaptation to metabolic and oxidative stresses by activation of autophagy, a crucial cellular catabolic pathway. Metabolic stress can lead to changes in the redox state of nicotinamide adenine dinucleotide (NAD), a co-factor in a variety of enzymatic reactions and thus trigger autophagy that acts to sequester intracellular components for recycling to support cellular growth. Likewise, autophagy is activated by oxidative stress to selectively recycle damaged macromolecules and organelles and thus maintain cellular viability. Multiple proteins that help regulate or execute autophagy are targets of post-translational modifications (PTMs) that have an effect on their localization, binding affinity or enzymatic activity. These PTMs include acetylation, a reversible enzymatic modification of a protein’s lysine residues, and oxidation, a set of reversible and irreversible modifications by free radicals. Here we highlight the latest findings and outstanding questions on the interplay of autophagy with metabolic stress, presenting as changes in NAD levels, and oxidative stress, with a focus on autophagy proteins that are regulated by both, oxidation and acetylation. We further explore the relevance of this multi-layered signalling to healthy human ageing and their potential role in human disease.
Highlights
nicotinamide adenine dinucleotide (NAD) depletion, oxidative stress and loss of macroautophagy efficiency have all been linked to healthy, pathological and premature ageing (Kubben and Misteli 2017; Lopez-Otın et al 2013, 2016)
We first explored the latest findings on how two post-translational modifications (PTMs), Lys acetylation and Cys oxidation, regulate the localization and function of autophagy proteins
Novel findings published in 2015–2020 identify TFEB, Unc-51-like kinase 1 (ULK1), VPS34, ATG3, LC3 and p62 as targets of acetylation PTMs which, in response to metabolic cues, stimulate the expression and enzymatic activity of autophagy proteins and improve pathway selectivity
Summary
NAD depletion, oxidative stress and loss of macroautophagy (from referred to as autophagy) efficiency have all been linked to healthy, pathological and premature ageing (Kubben and Misteli 2017; Lopez-Otın et al 2013, 2016). The canonical pathway of starvation-induced autophagy was long thought to rely on phosphorylation cascades that are triggered by the loss of nutrient signalling and converge on a small number of regulating kinase complexes (Beurel et al 2015; Rabanal-Ruiz et al 2017; Tamargo-Gomez and Marino 2018) These regulators either lose function and release downstream autophagy components from an inhibitory state, or become activated and promote autophagy initiation. Protein acetylation status is balanced by the activity of multiple lysine acetyl transferases
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