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Review
. 2018 Nov:83:36-41.
doi: 10.1016/j.semcdb.2018.03.012. Epub 2018 Apr 5.

"V体育2025版" Role of autophagy in IL-1β export and release from cells

Aurore Claude-Taupin  1 , Bhawana Bissa  1 , Jingyue Jia  1 , Yuexi Gu  1 , Vojo Deretic  2
Affiliations
Review

"VSports手机版" Role of autophagy in IL-1β export and release from cells

Aurore Claude-Taupin et al. Semin Cell Dev Biol. 2018 Nov.

Abstract

The autophagy pathway known also as macroautophagy (herein referred to as autophagy) is characterized by the formation of double-membrane organelles that capture cytosolic material. Based on pathway termination alternatives, autophagy has been divided into degradative and secretory VSports手机版. During degradative autophagy, autophagosomes typically fuse with lysosomes upon which the sequestered material is degraded. During secretory autophagy, instead of degradation the sequestered cargo is subjected to active secretion or passive release. In this review, we focus on the mechanisms of secretion/passive release of the potent pro-inflammatory cytokine IL-1β, as a prototypical leaderless cytosolic protein cargo studied in the context of secretory autophagy. .

Keywords: Autophagy; GSDMD; IL-1; Pyroptosis; Secretion; TRIM16 V体育安卓版. .

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Proposed mechanisms of unconventional IL-1β secretion
A. Chaperone (HSP90) mediated translocation of mature IL-1β into LC3-positive profiles with subsequent exocytosis at plasma membrane. Note that IL-1β in this model remains in the intermembrane space within the double membrane autophagosomes and that upon putative fusion at the plasma membrane IL-1β is free to diffuse. B. Lysosomal damage (a physiological inducer of inflammasome) activates canonical inflammasome and processing of pro-IL-1β into mature IL-1β (see details in panel C) after which mIL-1β is captured by the secretory autophagy receptor TRIM16. TRIM16 has four relevant features: (i) it recognizes local lysosomal damage via its binding to Galectin-8 (which in turn recognizes exposure of lumenal glycoconjugates to cytosol following membrane damage); (ii) it binds to mIL-1β and thus collect its after inflammasome activation; (iii) it associates with mammalian Atg8s (mAtg8s) such as GABARAP; and (iv) it binds via its SNC1/longin hybrid SNARE-like domain to the R-SNARE Sec22b on ERGIC and LC3+ membranes. The complex also contains HSP90 providing a potential link to the chaperone mediated translocation mechanism depicted in panel A (denoted by number 1). The Sec22b- TRIM16 complex with mIL-1β on LC3/mAtg8-positive vesicles can lead to lumenal sequestration of mIL-1β into double membrane autophagosomes once a phagophore forms and closes (net result denoted by number 2) with Sec22b forming 4-helix bundle SNARE complexes with Qa (STX3 or STX4) and Qbc (SNAP23 or SNAP29) SNAREs at the plasma membrane allowing exocytosis and secretion (denoted by number 3). Alternatively or in addition, Sec22b, previously described as being able to tether membranes to plasma membrane without fusion, could position/concentrate TRIM16-mIL-1β complexes at the plasma membrane for pore secretion/translocation/release mechanisms such as those described in model C. C. A gasdermin (GSDMD)-based model of IL-1β release. Non-canonical inflammasome activation associated with pyroptotic cell death following recognition of microbal products such as LPS when present directly in the cytoplasm, is mediated via Caspases 4, 5 and 11. These capsases process GSDMD to release GSDMD N-terminal domain/fragment (GSDMD-NT), which assembles into complexes/pores on cytoplasmic of still unknown nature, and GSDMD-NT pores are delivered to the plasma membrane causing plasma membrane permeability and pyroptotic cell death. Recent data indicate that GSDMD-NT at the plasma membrane can act independently of cell death and indiscriminate plasma membrane permeability (depicted below dashed line) by selectively exporting IL-1β from hyperactivated macrophages that are still alive into the extracellular milieu (depicted above the dashed line). This mechanism can also apply to canonical inflammasome activation, as caspase-1 (activated through conventional inflammasome mechanisms, e.g. as in panel B) can also process GSDMD. Note: Whereas the three mechanisms depicted in A-C may appear independent, the role of autophagy is implicated in all of them starting with the regulation of inflammasome activation and ending with known (e.g. HSP90 and Sec22b in A and B) or potential overlaps between B and C discussed in the text.
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