Oligomeric states of ASC specks regulate inflammatory responses by inflammasome in the extracellular space

Abstract

Inflammasomes are multi-protein complexes and play a crucial role in host defense against pathogens. Downstream inflammatory responses through inflammasomes are known to be related to the oligomerization degree of ASC specks, but the detailed mechanism still remains unexplored. Here, we demonstrate that oligomerization degrees of ASC specks regulate the caspase-1 activation in the extracellular space. A protein binder specific for a pyrin domain (PYD) of ASC (ASCPYD) was developed, and structural analysis revealed that the protein binder effectively inhibits the interaction between PYDs, disassembling ASC specks into low oligomeric states. ASC specks with a low oligomerization degree were shown to enhance the activation of caspase-1 by recruiting and processing more premature caspase-1 through interactions between CARD of caspase-1 (caspase-1CARD) and CARD of ASC (ASCCARD). These findings can provide insight into controlling the inflammasome-mediated inflammatory process as well as the development of inflammasome-targeting drugs.

Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC

“…Accordingly, it is envisaged that conjugation of SUMO1 at this location would obstruct the formation of the ASC filament unless this was subsequently removed by a SUMO1 protease. Interestingly, it has been shown by others that disruption of protein binding at the PYD of ASC promotes inflammasome activity by increasing the recruitment of pro-Caspase-1 via the proteins’ mutual CARDs 43 . Conceivably, SUMOylation of ASC’s PYD might function in this way to promote inflammasome assembly.…”

The NLRP3 inflammasome in viral infection (Review)

“…ASC contains two death-fold domains: One PYD and one CARD. The interaction between the upstream inflammasome sensor molecules triggers ASC assembly via the pyrin domain into a large protein complex ( 11 , 12 ). ASC brings procaspase 1 into close proximity with CARD, which initiates caspase 1 self-cleavage and activation ( 13 , 14 ).…”