Translocation of Interleukin-1β into a Vesicle Intermediate in Autophagy-mediated Secretion

Overview

Journal Elife

Specialty Biology

Date 2015 Nov 3

PMID 26523392

Citations 191

Authors

Min Zhang

Samuel J Kenny

Liang Ge

Ke Xu

Randy Schekman

Affiliations

Soon will be listed here.

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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References

Nickel W . The mystery of nonclassical protein secretion. A current view on cargo proteins and potential export routes. Eur J Biochem. 2003; 270(10):2109-19. DOI: 10.1046/j.1432-1033.2003.03577.x. View

Yang Z, Klionsky D . Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol. 2009; 22(2):124-31. PMC: 2854249. DOI: 10.1016/j.ceb.2009.11.014. View

Qu Y, Franchi L, Nunez G, Dubyak G . Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages. J Immunol. 2007; 179(3):1913-25. DOI: 10.4049/jimmunol.179.3.1913. View

Liu T, Yamaguchi Y, Shirasaki Y, Shikada K, Yamagishi M, Hoshino K . Single-cell imaging of caspase-1 dynamics reveals an all-or-none inflammasome signaling response. Cell Rep. 2014; 8(4):974-82. DOI: 10.1016/j.celrep.2014.07.012. View

Ge L, Baskaran S, Schekman R, Hurley J . The protein-vesicle network of autophagy. Curr Opin Cell Biol. 2014; 29:18-24. DOI: 10.1016/j.ceb.2014.02.005. View

Pfeffer S . Unconventional secretion by autophagosome exocytosis. J Cell Biol. 2010; 188(4):451-2. PMC: 2828920. DOI: 10.1083/jcb.201001121. View

Duran J, Anjard C, Stefan C, Loomis W, Malhotra V . Unconventional secretion of Acb1 is mediated by autophagosomes. J Cell Biol. 2010; 188(4):527-36. PMC: 2828925. DOI: 10.1083/jcb.200911154. View

Deretic V, Jiang S, Dupont N . Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation. Trends Cell Biol. 2012; 22(8):397-406. PMC: 3408825. DOI: 10.1016/j.tcb.2012.04.008. View

Nickel W, Rabouille C . Mechanisms of regulated unconventional protein secretion. Nat Rev Mol Cell Biol. 2009; 10(2):148-55. DOI: 10.1038/nrm2617. View

10.

Thornberry N, Bull H, Calaycay J, Chapman K, Howard A, Kostura M . A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992; 356(6372):768-74. DOI: 10.1038/356768a0. View

11.

Kaushik S, Cuervo A . Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 2012; 22(8):407-17. PMC: 3408550. DOI: 10.1016/j.tcb.2012.05.006. View

12.

Ostrowski M, Carmo N, Krumeich S, Fanget I, Raposo G, Savina A . Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2009; 12(1):19-30. DOI: 10.1038/ncb2000. View

13.

Huang B, Babcock H, Zhuang X . Breaking the diffraction barrier: super-resolution imaging of cells. Cell. 2010; 143(7):1047-58. PMC: 3272504. DOI: 10.1016/j.cell.2010.12.002. View

14.

Manjithaya R, Anjard C, Loomis W, Subramani S . Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation. J Cell Biol. 2010; 188(4):537-46. PMC: 2828923. DOI: 10.1083/jcb.200911149. View

15.

Backhaus R, Zehe C, Wegehingel S, Kehlenbach A, Schwappach B, Nickel W . Unconventional protein secretion: membrane translocation of FGF-2 does not require protein unfolding. J Cell Sci. 2004; 117(Pt 9):1727-36. DOI: 10.1242/jcs.01027. View

16.

Subramani S, Malhotra V . Non-autophagic roles of autophagy-related proteins. EMBO Rep. 2013; 14(2):143-51. PMC: 3566844. DOI: 10.1038/embor.2012.220. View

17.

Majeski A, Dice J . Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol. 2004; 36(12):2435-44. DOI: 10.1016/j.biocel.2004.02.013. View

18.

Giuliani F, Grieve A, Rabouille C . Unconventional secretion: a stress on GRASP. Curr Opin Cell Biol. 2011; 23(4):498-504. DOI: 10.1016/j.ceb.2011.04.005. View

19.

Hubbi M, Hu H, Kshitiz , Ahmed I, Levchenko A, Semenza G . Chaperone-mediated autophagy targets hypoxia-inducible factor-1α (HIF-1α) for lysosomal degradation. J Biol Chem. 2013; 288(15):10703-14. PMC: 3624450. DOI: 10.1074/jbc.M112.414771. View

20.

Harris J, Hartman M, Roche C, Zeng S, OShea A, Sharp F . Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem. 2011; 286(11):9587-97. PMC: 3058966. DOI: 10.1074/jbc.M110.202911. View