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Pathway Description
Autophagy
Homo sapiens
Signaling Pathway
Created: 2025-04-02
Last Updated: 2025-04-22
Autophagy is a highly conserved, multistep lysosomal degradation pathway that plays a central role in cellular homeostasis by sequestering cytoplasmic proteins, damaged organelles, and macromolecules into double‑membrane autophagosomes for delivery to lysosomes where they are hydrolyzed and recycled as metabolic substrates ; under nutrient‑replete (fed) conditions, PI3K–AKT signaling promotes mTORC1 association with and inhibitory phosphorylation of the ULK1–ATG13–FIP200 autophagy‑initiating complex, whereas during energy or calcium stress (e.g., in the fasted state), calcium/calmodulin‑dependent protein kinase kinase 2 (CAMKK2) directly phosphorylates and activates AMPK, which in turn phosphorylates ULK1 to trigger phagophore formation in an mTOR‑independent manner. An increased AMP:ATP ratio activates AMPK and concurrently inhibits mTORC1, resulting in dephosphorylation and activation of ULK1 kinase activity to nucleate the phagophore. Activated ULK1 phosphorylates components of the class III PI3K complex—composed of Beclin‑1, VPS34, VPS15, and ATG14L— which generates localized pools of phosphatidylinositol‑3‑phosphate (PI3P) on ER‑derived omegasomes, recruiting WIPI2 and DFCP1 to scaffold phagophore expansion. Two ubiquitin‑like conjugation systems mediate phagophore membrane elongation: ATG12 is covalently conjugated to ATG5 and associates with ATG16L1 to form a multimeric complex that localizes to expanding membranes, whereas cytosolic LC3 (ATG8) is processed by ATG4, activated by ATG7, and conjugated to phosphatidylethanolamine to generate LC3‑II, which stably decorates both sides of the phagophore and serves as a docking site for autophagy receptors like p62/SQSTM1. Following membranous engulfment and phagophore closure, mature autophagosomes traffic along microtubules and fuse with late endosomes or directly with lysosomes—a process orchestrated by SNARE proteins (STX17, SNAP29, VAMP8), Rab7 GTPase, the HOPS tethering complex, and additional fusion regulators—to form autolysosomes in which sequestered cargo is degraded and recycled. The dynamic regulation of autophagy by nutrients, energy status, and stress signals not only sustains cellular survival during starvation but also contributes to tissue‐specific and endocrine metabolic functions. Dysregulation of autophagy has been implicated in a spectrum of human diseases, including metabolic disorders (insulin resistance, diabetes, obesity), cancer (where it can act as both a tumor suppressor and a survival mechanism), neurodegenerative conditions, and immune dysfunctions. Furthermore, in pathological contexts such as tumor cells exposed to photodynamic therapy, upregulation of cytoprotective autophagy can foster treatment resistance by removing damaged components and mitigating oxidative stress, highlighting autophagy modulation as both a therapeutic opportunity and challenge.
References
Autophagy References
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