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

Xu, Zhihao; Zhou, Ying; Liu, Muziying; Ma, Huan; Sun, Liangqi; Zahid, Ayesha; Chen, Yulei; Zhou, Rongbin; Cao, Min‐Jie; Wu, Dexiang; Zhao, Weidong; Li, Bofeng; Jin, Tengchuan

doi:10.1038/s41419-020-03342-8

Cited by 15 publications

(22 citation statements)

References 58 publications

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“…S2c and d). Our results are consistent with previous reports [20][21][22][23] that ASC is an indispensable, dispensable and independent adaptor in NLRP1, mNLRP1b and CARD8 inflammasome assembly, respectively.…”

Section: Distinct Asc Preference Is Dependent On Card But Not Upa Dom...supporting

confidence: 94%

“…More importantly, we also found that multiple molecular surfaces were involved in the interaction of NLRP1 UPA-CARD and Caspase-1 CARD to transduce downstream signals, which is consistent with the Mosaic model that DD superfamily members co-assemble into archetypical supramolecular platform by three conserved interaction types 21 (Fig. 5e and S3a-d).…”

Section: Structure Basis For Card Domain-mediated Asc Preferencesupporting

confidence: 88%

“…Constructs for entire coding sequence of ASC, proCaspase-1 and IL-1β were prepared as previously described 21 . The cDNA sequences of mNLRP1b (UniProt ID: Q2LKW6-1), NLRP1 (UniProt ID: Q9C000-1), CARD8-T48 (UniProt ID: Q9Y2G2-1) and CARD8-T60 (UniProt ID:…”

Section: Cloning and Reagentsmentioning

confidence: 99%

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CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1

Deng

Huang

et al. 2022

Preprint

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NLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the canonical T48 isoform, negatively regulates NLRP1 inflammasome activation by directly interacting with the receptor molecule NLRP1 and inhibiting inflammasome assembly. Furthermore, our results suggest that the different ASC preference in three types of inflammasomes, namely ASC-indispensable NLRP1 inflammasome, ASC-dispensable mNLRP1b inflammasome and ASC-independent CARD8 inflammasome, is mainly caused by the CARD domain, not the UPA subdomain. Based on the systematic site-directed mutagenesis and structural analysis, we find that the signal transduction of NLRP1 inflammasome relies on multiple interaction surfaces on its death domain superfamily member CARD domain. Finally, our results partly explain the mechanism of the NLRP1 mutation-derived auto-inflammatory diseases caused by the overactivation of the NLRP1 inflammasome. In conclusion, our study not only reveals how CARD8 downregulates NLRP1 inflammasome activation, but also provides insights into the mechanisms of CARD-containing inflammasome assembly.

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Section: Distinct Asc Preference Is Dependent On Card But Not Upa Dom...supporting

confidence: 94%

Section: Structure Basis For Card Domain-mediated Asc Preferencesupporting

confidence: 88%

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CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1

Deng

Huang

et al. 2022

Preprint

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“…The ASC dependence varies for each inflammasome, while pro-Casp-1 activation in NLRP3 and AIM2 inflammasomes requires ASC, the presence of ASC enhances pro-inflammatory signaling in CARD containing sensors, such as NLRP1 and NLRC4 [ 14 , 15 ]. Recently, structural studies showed direct interaction between NLRP1 CARD and ASC CARD and between NLRC4 CARD and ASC CARD [ 16 , 24 ]. As inflammatory responses depend on the activation of more than one inflammasome in several diseases [ 25 – 27 ], any drug that can inhibit numerous inflammasome complexes simultaneously would be of significant interest.…”

Section: Introductionmentioning

confidence: 99%

Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases

et al. 2021

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The ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) protein is an scaffold component of different inflammasomes, intracellular multiprotein platforms of the innate immune system that are activated in response to pathogens or intracellular damage. The formation of ASC specks, initiated by different inflammasome receptors, promotes the recruitment and activation of procaspase-1, thereby triggering pyroptotic inflammatory cell death and pro-inflammatory cytokine release. Here we describe MM01 as the first-in-class small-molecule inhibitor of ASC that interferes with ASC speck formation. MM01 inhibition of ASC oligomerization prevents activation of procaspase-1 in vitro and inhibits the activation of different ASC-dependent inflammasomes in cell lines and primary cultures. Furthermore, MM01 inhibits inflammation in vivo in a mouse model of inflammasome-induced peritonitis. Overall, we highlight MM01 as a novel broad-spectrum inflammasome inhibitor for the potential treatment of multifactorial diseases involving the dysregulation of multiple inflammasomes.

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“…Inflammasomes are made up of a sensor protein such as NLR containing protein that detects the danger signals and recruits adaptors such as ASC. ASC ultimately incorporates effector proteins into the assembly for example caspase-1 via homotypic death domain interactions which results in higher-order assembly of inflammasomes yielding activated caspases [4][5][6]. The NLR/ALR-containing inflammasome are often termed as canonical inflammasomes, for example, NLRP3 inflammasome.…”

Section: Introductionmentioning

confidence: 99%

Molecular and structural aspects of gasdermin family pores and insights into gasdermin-elicited programmed cell death

Zahid

Ismail

Jin

2021

Biochemical Society Transactions

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Pyroptosis is a highly inflammatory and lytic type of programmed cell death (PCD) commenced by inflammasomes, which sense perturbations in the cytosolic environment. Recently, several ground-breaking studies have linked a family of pore-forming proteins known as gasdermins (GSDMs) to pyroptosis. The human genome encodes six GSDM proteins which have a characteristic feature of forming pores in the plasma membrane resulting in the disruption of cellular homeostasis and subsequent induction of cell death. GSDMs have an N-terminal cytotoxic domain and an auto-inhibitory C-terminal domain linked together through a flexible hinge region whose proteolytic cleavage by various enzymes releases the N-terminal fragment that can insert itself into the inner leaflet of the plasma membrane by binding to acidic lipids leading to pore formation. Emerging studies have disclosed the involvement of GSDMs in various modalities of PCD highlighting their role in diverse cellular and pathological processes. Recently, the cryo-EM structures of the GSDMA3 and GSDMD pores were resolved which have provided valuable insights into the pore formation process of GSDMs. Here, we discuss the current knowledge regarding the role of GSDMs in PCD, structural and molecular aspects of autoinhibition, and pore formation mechanism followed by a summary of functional consequences of gasdermin-induced membrane permeabilization.

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

Cited by 15 publications

References 58 publications

CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1

CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1

Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases

Molecular and structural aspects of gasdermin family pores and insights into gasdermin-elicited programmed cell death

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