Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia

Robinson, Kim; Teo, Daniel Eng Thiam; Tan, Kai Sen; Toh, Gee Ann; Ong, Hsiao Hui; Lim, Chrissie; Lay, Kenneth; Au, Bijin; Lew, Tian Sheng; Chu, Justin Jang Hann; Chow, Vincent T. K.; Wang, De Yun; Zhong, Franklin L.; Reversade, Bruno

doi:10.1126/science.aay2002

Cited by 185 publications

(170 citation statements)

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“…1,3 ). This unique mechanism involving 'functional degradation' is conserved in the activation of human NLRP1 (hNLRP1) by the 3C proteases of enteroviruses 14 and in the activation of CARD8 by HIV-1 protease 15 .…”

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confidence: 99%

Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

Huang

Zhang

Toh

et al. 2021

Nature

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

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confidence: 99%

Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

Huang

Zhang

Toh

et al. 2021

Nature

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121

108

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“…Human nucleotide-binding domain leucine-rich repeat pyrin domain-containing 1 (hNLRP1) was the first PRR discovered to form an inflammasome (Martinon et al, 2002), but the danger signal that activates hNLRP1 has eluded identification for nearly 20 years. Two recent studies provide evidence that hNLRP1 directly senses (at least) two extraordinarily different things: enteroviral 3C protease activity (Robinson et al, 2020) and long double-stranded RNA (dsRNA) (Bauernfried et al, 2020).…”

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confidence: 99%

NLRP1: a jack of all trades, or a master of one?

Bachovchin

2021

Molecular Cell

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“…For example, CARD8 and NLRP1 may have evolved to respond to different pathogens. Consistent with this idea, recent reports revealed that human rhinovirus 3C protease and HIV protease directly cleave and activate human NLRP1 and CARD8, respectively (Robinson et al, 2020;Tsu et al, 2020;Wang et al, 2020). Moreover, human NLRP1 was also recently reported to sense intracellular long doublestranded RNAs by directly binding them through its leucine-rich repeat (LRR) domain (Bauernfried et al, 2020), which is absent in CARD8.…”

Section: Discussionmentioning

confidence: 72%

“…The inflammatory CT must be released from the repressive NT for CARD8 activation (Johnson et al, 2018). DPP8/9 inhibitors, including VbP, activate the CARD8 inflammasome in human macrophages and resting lymphocytes and the NLRP1 inflammasome in skin and airway epithelial cells (Johnson et al, 2020;Johnson et al, 2018;Linder et al, 2020;Robinson et al, 2020;Zhong et al, 2018). The mechanisms of DPP8/9 inhibitor-induced CARD8 and NLRP1 inflammasome activation have not yet been fully established.…”

Section: Introductionmentioning

confidence: 99%

Structural mechanism of CARD8 regulation by DPP9

Sharif

Hollingsworth

Griswold

et al. 2021

Preprint

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SUMMARYCARD8 is a germline-encoded pattern recognition receptor that detects intracellular danger signals. Like the related inflammasome sensor NLRP1, CARD8 undergoes constitutive autoprocessing within its function-to-find domain (FIIND), generating two polypeptides that stay associated and autoinhibited. Certain pathogen- and danger-associated activities, including the inhibition of the serine dipeptidases DPP8 and DPP9 (DPP8/9), induce the proteasome-mediated degradation of the N-terminal (NT) fragment, releasing the C-terminal (CT) fragment to form a caspase-1 activating inflammasome. DPP8/9 also bind directly to the CARD8 FIIND, but the role that this interaction plays in CARD8 inflammasome regulation is not yet understood. Here, we solved several cryo-EM structures of CARD8 bound to DPP9, with or without the DPP inhibitor Val-boroPro (VbP), which revealed a ternary complex composed of one DPP9, the full-length CARD8, and one CARD8-CT. Through structure-guided biochemical and cellular experiments, we demonstrated that DPP9’s structure restrains CARD8-CT after proteasomal degradation. Moreover, although DPP inhibitors do not directly displace CARD8 from DPP9 in vitro, we show that they can nevertheless destabilize this complex in cells. Overall, these results demonstrate that DPP8/9 inhibitors cause CARD8 inflammasome activation via at least two distinct mechanisms, one upstream and one downstream of the proteasome.

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Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia

Cited by 185 publications

References 56 publications

Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

NLRP1: a jack of all trades, or a master of one?

Structural mechanism of CARD8 regulation by DPP9

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