摘要

巨自噬/自噬是一种进化上保存完好的循环过程，可响应压力条件，包括活性氧 (ROS) 的大量产生。高水平的 ROS 攻击关键的细胞大分子。因此，蛋白质半胱氨酰硫醇或非蛋白质硫醇作为主要的氧化还原敏感靶标，构成了第一道防线。自噬是独一无二的，因为它不仅可以去除氧化/受损的蛋白质，还可以去除大量产生 ROS 的细胞器（如线粒体和过氧化物酶体），以限制进一步的 ROS 产生。自噬的氧化调控发生在自噬的所有过程中，从诱导、吞噬细胞成核、吞噬细胞扩增、自噬体成熟、货物运送到溶酶体，最后到货物的降解和产物的回收，以及自噬基因的转录。从机械上讲，这些规定是通过直接或间接的方式实现的。关键蛋白如 ATG4、ATM 和 TFEB 的直接硫醇氧化分别负责吞噬细胞扩增、货物识别和自噬基因转录的特定调节。同时，某些氧化还原敏感性伴侣蛋白的氧化（例如。PRDX 家族成员和 PARK7) 可能会损害吞噬细胞膜中非特异性的局部还原环境，并影响 BECN1 参与的吞噬细胞成核和线粒体识别。然而，ROS 确实通过直接氧化关键的自噬调节因子（如 ATG3、ATG7 和 SENP3 蛋白）对自噬产生了一些抑制作用。当自噬不可用或受损时，SQSTM1 提供了另一种抗氧化机制。然而，细胞如何进化以使蛋白质具有不同的氧化还原敏感性和正确的亚细胞位置，以及细胞如何微调自噬机制以响应不同水平的 ROS，还有待解开。

缩写： AKT1/PKB：AKT丝氨酸/苏氨酸激酶1；AMPK：AMP激活的蛋白激酶；ATG：自噬相关；ATM：ATM丝氨酸/苏氨酸激酶；BAX：BCL2 相关 X，凋亡调节剂；BECN1：beclin 1；BH3：BCL2-同源性-3；CAV1：小窝蛋白 1；CCCP：羰基氰间氯苯腙；CTSB：组织蛋白酶 B；CTSL：组织蛋白酶L；DAPK：死亡相关蛋白激酶；ER：内质网；ETC：电子传输链；GSH：谷胱甘肽；GSTP1：谷胱甘肽 S-转移酶 pi 1；H 2 O 2：过氧化氢；HK2：己糖激酶 2；KEAP1：kelch 样 ECH 相关蛋白 1；MAMs：线粒体相关的 ER 膜；MAP1LC3B/LC3：微管相关蛋白1轻链3β；MAPK8/JNK1：丝裂原活化蛋白激酶 8；MAP3K5/ASK1：丝裂原活化蛋白激酶激酶 5；MCOLN1：粘磷脂1；MMP：线粒体膜电位；MTOR：雷帕霉素激酶的机制靶点；NFE2L2/NRF2：核因子，红系2样2；NFKB1：核因子 kappa B 亚基 1；NOX：NADPH氧化酶；O 2-：超氧自由基阴离子；p-Ub：磷酸化 Ub；PARK7/DJ-1：帕金森病相关去糖酶；PE：磷脂酰乙醇胺；PEX5：过氧化物酶体生物发生因子 5；PINK1：PTEN 诱导激酶 1；PPP3CA/钙调神经磷酸酶：蛋白磷酸酶 3 催化亚基 β；PRDX：过氧还蛋白；PRKAA1：蛋白激酶 AMP 激活的催化亚基 α 1；PRKD/PKD：蛋白激酶 D；PRKN/parkin：parkin RBR E3泛素蛋白连接酶；PtdIns3K：III类磷脂酰肌醇3-激酶；PtdIns3P：3-磷酸磷脂酰肌醇；PTEN：磷酸酶和张力蛋白同源物；ROS：活性氧；SENP3：SUMO 特异性肽酶 3；SIRT1：sirtuin 1；SOD1：超氧化物歧化酶1；SQSTM1/p62：隔离体 1；SUMO：小泛素样修饰剂；TFEB：转录因子EB；TRAF6：TNF受体相关因子6；TSC2：TSC复合亚基2；TXN：硫氧还蛋白；TXNRD1：硫氧还蛋白还原酶 1；TXNIP：硫氧还蛋白相互作用蛋白；Ub：泛素；ULK1：unc-51 样自噬激活激酶 1。

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ABSTRACT

Macroautophagy/autophagy is an evolutionarily well-conserved recycling process in response to stress conditions, including a burst of reactive oxygen species (ROS) production. High level of ROS attack key cellular macromolecules. Protein cysteinyl thiols or non-protein thiols as the major redox-sensitive targets thus constitute the first-line defense. Autophagy is unique, because it removes not only oxidized/damaged proteins but also bulky ROS-generating organelles (such as mitochondria and peroxisome) to restrict further ROS production. The oxidative regulations of autophagy occur in all processes of autophagy, from induction, phagophore nucleation, phagophore expansion, autophagosome maturation, cargo delivery to the lysosome, and finally to degradation of the cargo and recycling of the products, as well as autophagy gene transcription. Mechanically, these regulations are achieved through direct or indirect manners. Direct thiol oxidation of key proteins such as ATG4, ATM and TFEB are responsible for specific regulations in phagophore expansion, cargo recognition and autophagy gene transcription, respectively. Meanwhile, oxidation of certain redox-sensitive chaperone-like proteins (e.g. PRDX family members and PARK7) may impair a nonspecifically local reducing environment in the phagophore membrane, and influence BECN1-involved phagophore nucleation and mitophagy recognition. However, ROS do exhibit some inhibitory effects on autophagy through direct oxidation of key autophagy regulators such as ATG3, ATG7 and SENP3 proteins. SQSTM1 provides an alternative antioxidant mechanism when autophagy is unavailable or impaired. However, it is yet to be unraveled how cells evolve to equip proteins with different redox susceptibility and in their correct subcellular positions, and how cells fine-tune autophagy machinery in response to different levels of ROS.

Abbreviations: AKT1/PKB: AKT serine/threonine kinase 1; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATM: ATM serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; BH3: BCL2-homology-3; CAV1: caveolin 1; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CTSB: cathepsin B; CTSL: cathepsin L; DAPK: death associated protein kinase; ER: endoplasmic reticulum; ETC: electron transport chain; GSH: glutathione; GSTP1: glutathione S-transferase pi 1; H2O2: hydrogen peroxide; HK2: hexokinase 2; KEAP1: kelch like ECH associated protein 1; MAMs: mitochondria-associated ER membranes; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MAPK8/JNK1: mitogen-activated protein kinase 8; MAP3K5/ASK1: mitogen-activated protein kinase kinase kinase 5; MCOLN1: mucolipin 1; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NFKB1: nuclear factor kappa B subunit 1; NOX: NADPH oxidase; O2-: superoxide radical anion; p-Ub: phosphorylated Ub; PARK7/DJ-1: Parkinsonism associated deglycase; PE: phosphatidylethanolamine; PEX5: peroxisomal biogenesis factor 5; PINK1: PTEN induced kinase 1; PPP3CA/calcineurin: protein phosphatase 3 catalytic subunit beta; PRDX: peroxiredoxin; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKD/PKD: protein kinase D; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; ROS: reactive oxygen species; SENP3: SUMO specific peptidase 3; SIRT1: sirtuin 1; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; SUMO: small ubiquitin like modifier; TFEB: transcription factor EB; TRAF6: TNF receptor associated factor 6; TSC2: TSC complex subunit 2; TXN: thioredoxin; TXNRD1: thioredoxin reductase 1; TXNIP: thioredoxin interacting protein; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1.