Plain-language summary
Autophagy is best known as the cell's recycling system, in which ATG8-family proteins decorate membranes to tag material for lysosomal degradation. Over the past decade it has become clear that the same machinery also ships proteins and other cargo out of the cell through routes collectively called secretory autophagy. This review summarizes how ATG8 proteins conjugated to different intracellular membranes — a process termed ATG8ylation — specify what gets released and steer it toward the cell surface. The authors propose a framework that classifies the expanding list of secretory autophagy pathways according to where ATG8ylated vesicular intermediates sit inside the cell, ranging from endosomes to single-membrane compartments. They also survey the emerging roles of these pathways in physiology and disease, including neurodegeneration and inflammation, and note their overlap with extracellular vesicle biology, since several routes load and release vesicles carrying signaling molecules.
Key findings
- ATG8-family proteins are conjugated to intracellular membranes (ATG8ylation) not only to mark cargo for degradation but also to route molecules for secretion from the cell.
- The review proposes a cell-biological framework that classifies secretory autophagy pathways by the intracellular vesicular intermediates where membrane ATG8ylation occurs.
- Several described routes overlap with extracellular vesicle biology, including LC3-dependent vesicle loading and secretion.
- Secretory autophagy pathways are increasingly implicated in inflammation, neurodegeneration and other disease settings.
Original abstract
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.
Frequently asked questions
What did this study find?
Autophagy is best known as the cell's recycling system, in which ATG8-family proteins decorate membranes to tag material for lysosomal degradation. Over the past decade it has become clear that the same machinery also ships proteins and other cargo out of the cell through routes collectively called secretory autophagy. This review summarizes how ATG8 proteins conjugated to different intracellular membranes — a process termed ATG8ylation — specify what gets released and steer it toward the cell surface. The authors propose a framework that classifies the expanding list of secretory autophagy pathways according to where ATG8ylated vesicular intermediates sit inside the cell, ranging from endosomes to single-membrane compartments. They also survey the emerging roles of these pathways in physiology and disease, including neurodegeneration and inflammation, and note their overlap with extracellular vesicle biology, since several routes load and release vesicles carrying signaling molecules.
Was this tested in humans or in the laboratory?
This is a review: it summarises and weighs up previously published studies rather than presenting new experiments.
Where can I read the original paper?
The full text lives with the publisher: https://doi.org/10.1080/15548627.2026.2676796
How to cite this paper
Debnath Jayanta, Leidal Andrew M. Membrane ATG8ylation in secretory autophagy.. Autophagy. 2026, 2026-05-25. DOI: 10.1080/15548627.2026.2676796
Source & verification
- Journal: Autophagy
- Published: 25 May 2026
- DOI: 10.1080/15548627.2026.2676796
- PubMed ID: 42178909
- Indexed via: pubmed
- MeSH terms: Autophagy, Humans, Animals, Autophagy-Related Protein 8 Family, Cell Membrane