Autophagy
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P193-194
2025-11-11
40
Autophagy is defined as “self-eating” and culminates in sequestration of the cytoplasmic material and organelles into a double-membrane structure, the autophagosome, which subsequently is delivered to the lysosome for degradation and recycling. Autophagy permits the cell to maintain homeostasis when faced with metabolic or environmental stressors, including hypoxia, nutrient deprivation, and cytotoxic chemotherapy. In mammals, the core autophagy machinery includes the Atg1-Ulk1 protein complex, which initiates autophagy by recruiting the class III PI3K complex, which is required for recruitment of autophagic factors. The core autophagy proteins, or ATGs, function to generate autophagosomes by encapsulating cytoplasmic cargo within a double-membrane vesicle. These autophagosomes subsequently fuse with acidic lysosomes, and the cytoplasmic material is degraded by pH-sensitive enzymes.
The multistep process of macroautophagy includes phagophore initiation, vesicle nucleation, vesicle elongation, and autophagosome fusion with lysosomes (Fig. 1). Phagophores, or isolation mem branes, are the precursors of autophagosomes. This pathway is initiated by the Unc-51–like kinase (ULK) complex, which phosphorylates a phosphatidylinositol 3-kinase, VPS34, which is part of the Beclin1 complex required for initiation of the phagophore. The ULK com plex can be regulated by nutrient availability via mTOR (mammalian target of rapamycin). Vesicle elongation depends on two ubiquitin (Ub)-like conjugation systems. ATG5 is conjugated to ATG12 by the E1-like enzyme ATG7 and the E2-like enzyme ATG10. The ATG5 ATG12 conjugate then binds to ATG16L1, and together they function as an E3-like enzyme (in coordination with ATG7 and ATG3) to facilitate the conjugation of the microtubule-associated LC3 family of proteins to phosphatidylethanolamine (PE). This second conjugation is also aided by ATG7 as well as the E1-like enzyme ATG3. Membrane-associated LC3-PE is incorporated into the autophagosome membrane. SNARE proteins, in conjunction with the small GTPases such as Rab7, facilitate fusion between fully formed autophagosomes and lysosomes. After fusion occurs, the cytoplasmic material within the autolysosome, as well as intravesicular LC3-II, is degraded by pH-sensitive enzymes found within the acidic compartments.
Fig1. AUTOPHAGY SIGNALING.
Regulation of autophagy under conditions of nutrient availability occurs primarily through the mammalian target of rapamycin complexes, mTORC1 and mTORC2, as well as 5′ AMP-activated protein kinase (AMPK). Under conditions of amino acid deprivation, mTORC complexes are unable to phosphorylate and inhibit the ULK system, and reduced energy translates into decreased ATP:AMP ratios that induce AMPK, which in turn inhibits mTORC and directly activates the ULK complex. Other cellular stressors, such as hypoxia, endo plasmic reticulum (ER) stress, and metabolic stress, generally regulate autophagy through the above-mentioned key nutrient-sensing path ways. Additionally, the basal autophagy state may be regulated transcriptionally through expression of the core ATGs; examples of transcription factors include TFEB, the forkhead family of transcription factors (FOXO1 and FOXO3), and the epigenetic regulator BRD4.
Tumor cells commonly have high metabolic demands and experience hypoxia and nutrient deficiencies; thus, they use autophagy to promote their survival. For example, under hypoxic conditions, stabilization of hypoxia-inducible factor 1 alpha (HIF1-α) induces activation of proapoptotic proteins that induce autophagy without triggering cell death.53 Similarly, under nutrient starvation, AMPK activates catabolic autophagy, providing nutrients that sustain tumor cell survival. Certain oncogenes, such as KRAS, when mutated, activate autophagy to support primary tumor growth and facilitate metastasis. This dependency on autophagy makes it an attractive therapeutic target, and several pharmacological autophagy inhibitors are in clinical development. Further, many cytotoxic agents and some targeted therapies, such as kinase inhibitors, have been shown to induce autophagy as a cytoprotective measure in cancer cells; thus, combinations of these agents with autophagy inhibitors may circumvent therapeutic resistance.
Other forms of autophagy include microautophagy (mainly in yeast and plants) and chaperone-mediated autophagy (CMA), which facilitates direct delivery to the lysosome. In CMA, substrates reach the lysosomes through LAMP2A translocation complexes at the lysosomal membrane; these are dismantled by lysosomal HSPA8, and the process does not require vesicles or membrane invagination. CMA is involved in multiple physiological and pathophysiological processes, such as metabolic regulation, aging, neurodegeneration, and T-cell activation, and recently has been implicated in tumorigenesis.
While in a number of settings autophagy may facilitate cellular demise, this is generally viewed as a failed attempt to support survival. However, autophagic cell death (i.e., a cell death relying on autophagic machinery) has been reported in epithelial cells transformed with RAS63 and in the setting of telomere dysfunction suggesting that in certain circumstances, autophagy might function to prevent oncogenic transformation.
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