The intra- and extracellular functions of ASC specks.

Abstract

Inflammasomes are the central signaling hubs of the inflammatory response. They process cytosolic evidence of infection, cell damage, or metabolic disturbances, and elicit a pro-inflammatory response mediated by members of the interleukin-1 family of cytokines and pyroptotoic cell death. On the molecular level, this is accomplished by the sensor-nucleated recruitment and oligomerization of the adapter protein ASC. Once a tunable threshold is reached, cooperative assembly of ASC into linear filaments and their condensation into macromolecular ASC specks promotes an all-or-none response. These structures are highly regulated and provide a unique signaling platform or compartment to control the activity of caspase-1 and likely other effectors. Emerging evidence indicates that ASC specks are also released from inflammasome-activated cells and accumulate in inflamed tissues, where they can continue to mature cytokines or be internalized by surrounding cells to further nucleate ASC specks in their cytosol. Little is known about the mechanisms governing ASC speck release, uptake, and endosomal escape, as well as its contribution to inflammation and disease. Here, we describe the different outcomes of inflammasome activation and discuss the potential function of extracellular ASC specks. We highlight gaps in our understanding of this central process of inflammation, which may have direct consequences on the modulation of host responses and chronic inflammation.