RT Journal Article
SR Electronic
T1 Structural and biochemical mechanisms of NLRP1 inhibition by DPP9
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.13.250241
DO 10.1101/2020.08.13.250241
A1 Menghang Huang
A1 Xiaoxiao Zhang
A1 Toh Gee Ann
A1 Qin Gong
A1 Jia Wang
A1 Zhifu Han
A1 Bin Wu
A1 Franklin Zhong
A1 Jijie Chai
YR 2020
UL http://biorxiv.org/content/early/2020/08/15/2020.08.13.250241.abstract
AB The nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires auto-cleavage within its FIIND domain1–7. In resting cells, the dipeptidyl peptidase DPP9 interacts with NLRP1-FIIND and together with a related enzyme DPP8, suppresses spontaneous NLRP1 activation8,9. The mechanisms of DPP8/9-mediated NLRP1 inhibition, however, remain elusive. Here we provide structural and biochemical evidence demonstrating that rat NLRP1 (rNLRP1) interacts with rDPP9 in a stepwise manner to form a 2:1 complex. An auto-inhibited rNLRP1 molecule first interacts with rDPP9 via its ZU5 domain. This 1:1 rNLRP1-rDPP9 complex then captures the UPA domain of a second rNLRP1 molecule via a UPA-interacting site on DPP9 and dimeric UPA-UPA interactions with the first rNLRP1. The 2:1 rNLRP1-rDPP9 complex prevents NLRP1 UPA-mediated higher order oligomerization and maintains NLRP1 in the auto-inhibited state. Structure-guided biochemical and functional assays show that both NLRP1-binding and its enzymatic activity are required for DPP9 to suppress NLRP1, supporting guard-type activation of the NLR. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on activation of the NLRP1 inflammasome.Competing Interest StatementThe authors have declared no competing interest.