Translocation of interleukin-1β into a vesicle intermediate in autophagy-mediated secretion

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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.

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Min Zhang

Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Sam Kenny

Department of Chemistry, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Liang Ge

Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Ke Xu

Department of Chemistry, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Randy Schekman

Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States

For correspondence
schekman@berkeley.edu

Competing interests
Randy Schekman, Editor-in-Chief, eLife.

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