Under the ROS: Thiol network is the principal suspect for autophagy commitment

Abstract

and ciriolo@bio.uniroma2.it L ow molecular weight and protein sulphydryls undergo reactive oxygen species (ROS)-mediated oxidation. However, in contrast to the irreversible damages that oxidative conditions yield on biomolecules, the oxidation of reactive cysteines frequently results in reversible modifications, which represent the prototype of the molecular mechanisms underlying redox signaling. Many proteins involved in a wide range of cellular processes have been classified as "redoxsensitive," thereby modulating their function/activity dependent on the redox state of their critical thiols. Growing evidence from the past few years supports the idea that ROS production also correlates with the occurrence of autophagy. Nonetheless, the cysteine protease Atg4 remains the sole example of a protein whose redox regulation has been completely characterized and demonstrated to be necessary for the progression of autophagy. The principal aim of this commentary is to draw attention to the remarkable number of proteins that can fit the double role of: (i) being involved in autophagy, especially in autophagosome formation and (ii) sensing alterations of the cellular redox state by means of reactive cysteine residues. We will also attempt to provide a hypothetical model to explain the possible functional role of thiols in the occurrence of autophagy and outline a network of redox reactions likely concurring to allow the correct initiation and completion of autophagosomes.

Negative regulation of autophagy by sulfide in Arabidopsis thaliana is independent of reactive oxygen species

“…Therefore, two questions arise: whether S-sulfhydration regulates autophagy, and what are the specific targets of sulfide. The thiol redox state can profoundly influence autophagy, especially during the initiation and completion of autophagosomes, due to the ability of several proteins that are involved in autophagy to sense alterations in the cellular redox state by means of reactive Cys residues (Filomeni et al, 2010). Examples of this are the ubiquitinlike systems ATG7-ATG10 and ATG7-ATG3, the functions of which rely on the Cys-based transfer of ATG12 and ATG8, respectively, which are essential proteins for autophagosome membrane elongation (Filomeni et al, 2010).…”

“…The thiol redox state can profoundly influence autophagy, especially during the initiation and completion of autophagosomes, due to the ability of several proteins that are involved in autophagy to sense alterations in the cellular redox state by means of reactive Cys residues (Filomeni et al, 2010). Examples of this are the ubiquitinlike systems ATG7-ATG10 and ATG7-ATG3, the functions of which rely on the Cys-based transfer of ATG12 and ATG8, respectively, which are essential proteins for autophagosome membrane elongation (Filomeni et al, 2010). Moreover, redox regulation of the Cys protease ATG4 has been characterized in detail in mammalian systems, and a Cys residue located near the catalytic site has been found to be critical for this regulation (Scherz-Shouval et al, 2007).…”

MAPK14/p38α-dependent modulation of glucose metabolism affects ROS levels and autophagy during starvation

“…48 In particular, NADPH participates in the maintenance of glutathione homeostasis, 49 a crucial determinant of the cellular redox balance, whose alteration modulates a plethora of cellular mechanisms, including autophagy, as we have demonstrated in previous works. 27,50 From this point of view, the modulation of autophagy could be at the basis of the protective effect of MAPK14 on starvation-induced cell death. In fact, although autophagy is a well-known protective mechanism that contributes to maintain cell viability by providing substrates for ATP production and macromolecules synthesis through the self-digestion of cellular components, an uncontrolled activation of autophagy may, on the contrary, be detrimental and could finally give rise to cell death.…”

“…1B and C). Nutrient starvation is known to induce a massive increase of ROS levels, 27,28 and MAPK14 is a well-recognized redox-responsive protein kinase. 17,29,30 Therefore, to evaluate whether MAPK14 phosphoactivation was dependent on ROS production, we pretreated cells for one h with 5 mM of N-acetyl-l-cysteine (NAC), a well-known antioxidant molecule.…”

Redox implications of AMPK-mediated signal transduction beyond energetic clues

“…Autophagy has a role in the maintenance of tissue homeostasis and in the response to environmental stresses; moreover, this process is often deregulated in various human diseases, such as neurodegeneration and cancer (Cecconi and Levine, 2008). Growing evidence supports the idea that redox imbalance affects autophagy, especially during autophagosome elongation (Filomeni et al, 2010a Fig. 3.…”