Table 1.

Essential autophagy proteins that are susceptible to oxidative stress directly or indirectly

Protein or pathway	Essential residues	Basal function	Effects after oxidation	Ref.
Autophagy initiation and phagophore nucleation
PRKAA1/AMPK-BECN1	Cys299 and Cys304 of PRKAA1	AMPK inhibits MTOR and in turn activates ULK1 and BECN1.	Cys-oxidation may cause AMPK activation and downstream BECN1 phosphorylation. AMPK oxidation is still debatable.	[48]
ATM-TSC2-BECN1	Cys2991 of ATM	Cytosol ATM can phosphorylate TSC2 independent of DNA damage.	ATM oxidation may facilitate its recruitment by PEX5 to peroxisome surface where it phosphorates TSC2. TSC2 phosphorylation then turns on BECN1-invovled autophagy.	[35]
MAPK8/JNK1-BCL2-BECN1		BCL2 binds with BECN1 to form an inhibitory complex. But MAPK8/JNK1-induced BCL2 phosphorylation releases BECN1 to induce autophagy.	BCL2 Phosphorylation by redox-sensitive MAPK8/JNK1 abolishes the inhibitory BCL2-BECN1 complex. The released BECN1 then initiates autophagy.	[40]
PRDX1-TRAF6-BECN1		TRAF6 ubiquitinates BECN1 at Lys117 to release it from inhibitory binding with BCL2.	ROS oxidizes PRDX1 to releases TRAF6 from their inhibitory binding. TRAF6 then facilitates BECN1 ubiquitination and subsequent release from inhibitory binding with BCL2.	[50]
SENP3-BECN1	Cys243 and Cys274 of SENP3	SENP3 removes SUMO modification from Lys380 of BECN1 and in turn inhibits PtdIns3K formation.	Cys-oxidation of SENP3 increases its binding with HSP90 which stabilizes SENP3. SENP3-mediated BECN1 deSUMOylation has poorer affinity with UVRAG to form PtdIns3K complex.	[52]
PTEN-AKT1-MTOR	Cys124 of PTEN	PTEN is a PtdIns(3,4,5)P3 3-phosphatase. It restrains AKT1 and its downstream signaling.	Oxidation of PTEN by H2O2 forms a disulfide bond between Cys124 and Cys71. PTEN oxidation decrease its phosphatase activity but enable AKT1 and MTOR activation.	[34]
Phagophore expansion
ATG4A ATG4B	Cys81 Cys78, Cys292, and Cys361	Cysteine protease ATG4 processes pro-Atg8 family proteins. It also deconjugates Atg8 from membrane-residing PE to limit phagophore expansion.	Cys-oxidations on ATG4 revert the inhibitory activity of ATG4 on LC3 lipidation, which in turn induces phagophore expansion	[53,56]
ATG7 ATG3	Cys572 Cys264	E1-like ATG7 activates ATG4-processed Atg8 family proteins; E2-like ATG3 then conjugates activated Atg8 to membrane-associated PE.	Cys-oxidations on ATG7 and ATG3 prevent LC3 lipidation.	[59]
Cargo recognition
ATM-PEX5-SQSTM1 inpexophagy	Cys2991 of ATM	Ubiquitinated PEX5 is a “eat-me” signal on peroxisome surface and it interacts with SQSTM1 to induce pexophagy.	Cys-oxidation on ATM facilitates its recruitment by peroxisome PEX5. ATM phosphorylates PEX5 at Ser141 and enable its subsequent ubiquitination at Lys209 as a “eat-me” signal.	[70]
ATM-? in mitophagy	Cys2991 of ATM	ATM resides in mitochondria and deletion of Atm causes impaired mitophagy.	The role of ATM oxidation is not tested yet in mitophagy. And the downstream “eat-me” signal in mitophagy is unknown.	[69]
Autophagy maturation
CTSL		CTSL is involved in enzymatic digestion in the last process of autophagy maturation.	In response to ROS, the hydrolytic activity of CTSL is decreased.	[80]
Transcriptional regulation
TFEB TFE3 MITF	Cys212 Cys322 Cys281	TFEB and family members are master transcription factors for genes involved in lysosomal and autophagic biogenesis.	Cys-oxidations promote TFEB nuclear translocation and its transcription activity.	[82]
MCOLN1-Ca2+- PPP3-TFEB		MCOLN1 is a lysosomal Ca2+-conducting receptor potential channel that releases Ca2+ into cytosol.	In response to ROS, MCOLN1 is activated and it releases Ca2+ into cytosol, which in turn activate PPP3, TFEB dephosphorylation and nuclear translocation.	[7]