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

TLDR

Autophagy has been implicated in the unconventional secretion of the pro‑inflammatory cytokine interleukin‑1β (IL‑1β). The study reconstituted autophagy‑regulated secretion of mature IL‑1β (m‑IL‑1β) in non‑macrophage cells. In the reconstituted system, m‑IL‑1β translocates across a membrane—requiring unfolding or flexibility and two KFERQ‑like motifs for HSP90 binding—before entering a vesicle intermediate that later matures into an autophagosome. IL‑1β associates with autophagosomes, localizes to the lumen of a vesicle precursor that becomes an autophagosome, and its secretion is completed only after GRASP‑mediated Golgi reassembly and multivesicular body formation.

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.