Autophagy. 2026 May 24.
1-16
Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.Abbreviations: Aβ, amyloid-β; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A1; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.
Keywords: ATG8ylation; extracellular vesicles and particles; noncanonical autophagy; secretory autophagy; unconventional protein secretion