title: Translocation of interleukin-1β into a vesicle intermediate in autophagy-mediated secretion.
abstract: Recent evidence suggests that autophagy facilitates the unconventional secretion of the pro-inflammatory cytokine interleukin 1β (IL-1β). Here, we reconstituted an autophagy-regulated secretion of mature IL-1β (m-IL-1β) in non-macrophage cells. We found that cytoplasmic IL-1β associates with the autophagosome and m-IL-1β enters into the lumen of a vesicle intermediate but not into the cytoplasmic interior formed by engulfment of the autophagic membrane. In advance of secretion, m-IL-1β appears to be translocated across a membrane in an event that may require m-IL-1β to be unfolded or remain conformationally flexible and is dependent on two KFERQ-like motifs essential for the association of IL-1β with HSP90. A vesicle, possibly a precursor of the phagophore, contains translocated m-IL-1β and later turns into an autophagosome in which m-IL-1β resides within the intermembrane space of the double-membrane structure. Completion of IL-1β secretion requires Golgi reassembly and stacking proteins (GRASPs) and multi-vesicular body (MVB) formation.
authors.affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of California, Berkeley, Berkeley, United States.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Kenny
authors.affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Liang
authors.identifier: http://orcid.org/0000-0002-7371-2039
authors.initials: L
authors.lastname: Ge
authors.affiliation: Department of Chemistry, University of California, Berkeley, Berkeley, United States.
authors.forename: Ke
authors.identifier: http://orcid.org/0000-0002-2788-194X
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
authors.forename: Randy
authors.identifier: http://orcid.org/0000-0001-8615-6409
authors.initials: R
authors.lastname: Schekman
mesh_terms: D020816:Amino Acid Motifs; D001343:Autophagy; D001665:Binding Sites; D002460:Cell Line; D022162:Cytoplasmic Vesicles / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport
chemical_list: D018841:HSP90 Heat-Shock Proteins; D053583:Interleukin-1beta
keywords: HSP90; autophagosome; autophagy; biochemistry; cell biology; human; interleukin-1β; mouse; unconventional secretion