Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

• DOI: 10.1038/s41586-021-03320-w
• Publication Date: 2021-03-17T17:02:46Z
• Authors: Menghang Huang; Xiaoxiao Zhang; Gee Ann Toh; Qin Gong; Jia Wang; Zhifu Han; Bin Wu; Franklin Zhong; Jijie Chai
• Keywords: NLRP1

Nucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND)1-7. In resting cells, dipeptidyl peptidases DPP8 and DPP9 interact with FIIND suppress spontaneous activation8,9; however, mechanisms through which this occurs remain unknown. Here we present structural biochemical evidence that full-length rat (rNLRP1) (rDPP9) form a 2:1 complex contains an autoinhibited rNLRP1 molecule active UPA-CARD fragment rNLRP1. The ZU5 is required not only for autoinhibition but also assembly complex. Formation prevents UPA-mediated higher-order oligomerization fragments strengthens ZU5-mediated autoinhibition. Structure-guided functional assays show both binding enzymatic activity are to in human cells. Together, our data reveal mechanism DPP9-mediated inhibition shed light on activation inflammasome.