Activation and assembly of the inflammasomes through conserved protein domain families

Abstract

Inflammasomes are oligomeric protein complexes assembled through interactions among the death domain superfamily members, in particular the CARD and PYD domains. Recent progress has shed lights on how the ASC PYD can polymerize to form filaments using multiple domain:domain interfaces, and how the caspase4 CARD can recognize LPS to activate the non-classical inflammasome pathway. Comprehensive understanding of the molecular mechanisms of inflammasome activation and assembly require more extensive structural and biophysical dissection of the inflammasome components and complexes, in particular additional CARD or PYD filaments. Because of the variations in death domain structures and complexes observed so far, future work will undoubtedly shed lights on the mechanisms of inflammasome assembly as well as more surprises on the versatile structure and function of the death domain superfamily.

Fig. 1

Cartoon presentation of inflammasome assembly. a Individual domains involved in inflammasome. Different domains were defined by distinct colors and shapes. b Resting states of the inflammasome components. c Domain organization for two of the best-studied inflammasomes in their activated states. Activated caspase domains are denoted with stars

Fig. 2

Structures of death domain superfamily members involved in inflammasome assembly. a Structure superposition of the CARDs from NLRP1 (cyan) and ASC (green). b Superposition of PYD structures onto the PYD of ASC. The ASC PYD structure is colored in grey and presented in the same orientation for all the panels. c Cryo-EM structure of the ASC PYD clusters in two different views