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Autophagy‐based unconventional secretory pathway for extracellular delivery of IL‐1β
Open accessAbstract
Autophagy controls the quality and quantity of the eukaryotic cytoplasm while performing two evolutionarily highly conserved functions: cell-autonomous provision of energy and nutrients by cytosol autodigestion during starvation, and removal of defunct organelles and large aggregates exceeding the capacity of other cellular degradative systems. In contrast to these autodigestive processes, autophagy in yeast has additional, biogenesis functions. However, no equivalent biosynthetic roles have been described for autophagy in mammals. Here, we show that in mammalian cells, autophagy has a hitherto unappreciated positive contribution to the biogenesis and secretion of the proinflammatory cytokine IL-1β via an export pathway that depends on Atg5, inflammasome, at least one of the two mammalian Golgi reassembly stacking protein (GRASP) paralogues, GRASP55 (GORASP2) and Rab8a. This process, which is a type of unconventional secretion, expands the functional manifestations of autophagy beyond autodigestive and quality control roles in mammals. It enables a subset of cytosolic proteins devoid of signal peptide sequences, and thus unable to access the conventional pathway through the ER, to enter an autophagy-based secretory pathway facilitating their exit from the cytoplasm.
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“Autophagy has also been recognized to mediate the secretion of proteins (34) – such as IL-1β and IL-18 (35, 36) – that would otherwise not enter the classical secretory pathway due to lack of a leader peptide.”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [35]
In the citing paper
“IL-18 trafficking is similar to that of IL-1β, with secretory autophagy also playing a major role in its release (35, 36).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [35]
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“Lack of fever induction may be explained by the fact that IL-18 signals through the MAPK p38 pathway instead of the NF-κB pathway, which is used by IL-1β (54).”
BackgroundInfluential
Metadata
- Authors
- Dupont, N., Jiang, S., Pilli, M., Ornatowski, W., Bhattacharya, D., & Deretic, V.
- Affiliations
- University of New Mexico Health Sciences Center (US)
- University of New Mexico (US)
- Corresponding author
- Deretic, Vojo
- ORCID
- Venue
- The EMBO Journal
- Published
- 2011-11-08
- Volume
- 30
- Issue
- 23
- Pages
- 4701-4711
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC3243609
- OpenAlex
- W2109070574
- Cited by
- 967
- References
- 68
- Citations by year
- 2026: 41 · 2025: 68 · 2024: 63 · 2023: 54 · 2022: 96 · 2021: 73 · 2020: 86 · 2019: 55 · 2018: 68 · 2017: 66 · 2016: 77 · 2015: 50 · 2014: 56 · 2013: 66 · 2012: 45
- FWCI
- 40.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AI042999)
- National Institute of Allergy and Infectious Diseases (RC1AI086845, R01AI042999, R01AI069345, R37AI042999)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- autophagy, unconventional secretion, IL-1β, proinflammatory cytokine secretion, ATG5, inflammasome, GRASP55, Rab8a
- MeSH terms
- Autophagy-Related Protein 5, Animals, Autophagy, Carrier Proteins, Cells, Cultured, Luminescent Proteins, Macrophages, Membrane Proteins, Microtubule-Associated Proteins, Nigericin, Protein Processing, Post-Translational, Macrolides, Interleukin-18, rab GTP-Binding Proteins, Protein Transport, HMGB1 Protein, Intracellular Signaling Peptides and Proteins, Mice, Interleukin-1beta, Secretory Pathway, Inflammasomes
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