Homotypic CARD-CARD interaction is critical for the activation of NLRP1 inflammasome

• Main Authors: Zhihao Xu, Ying Zhou, Muziying Liu, Huan Ma, Liangqi Sun, Ayesha Zahid, Yulei Chen, Rongbin Zhou, Minjie Cao, Dabao Wu, Weidong Zhao, Bofeng Li, Tengchuan Jin
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-01-01
• Series: Cell Death and Disease
• Online Access: https://doi.org/10.1038/s41419-020-03342-8

Abstract Cytosolic inflammasomes are supramolecular complexes that are formed in response to intracellular pathogens and danger signals. However, as to date, the detailed description of a homotypic caspase recruitment domain (CARD) interaction between NLRP1 and ASC has not been presented. We found the CARD–CARD interaction between purified NLRP1CARD and ASCCARD experimentally and the filamentous supramolecular complex formation in an in vitro proteins solution. Moreover, we determined a high-resolution crystal structure of the death domain fold of the human ASCCARD. Mutational and structural analysis revealed three conserved interfaces of the death domain superfamily (Type I, II, and III), which mediate the assembly of the NLRP1CARD/ASCCARD complex. In addition, we validated the role of the three major interfaces of CARDs in assembly and activation of NLRP1 inflammasome in vitro. Our findings suggest a Mosaic model of homotypic CARD interactions for the activation of NLRP1 inflammasome. The Mosaic model provides insights into the mechanisms of inflammasome assembly and signal transduction amplification.