Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation

Holliday, Michael J.; Witt, Axel; Gama, Alejandro Rodriguez; Walters, Benjamin T.; Arthur, Christopher P.; Halfmann, Randal; Rohou, Alexis; Dueber, Erin C.; Fairbrother, Wayne J.

doi:10.1038/s41467-019-10953-z

Cited by 36 publications

(76 citation statements)

References 73 publications

(103 reference statements)

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“…5a, b to Fig. 4c, d ), which had not been highlighted by previous analyses 24 , 29 , 34 – 40 . In ASC-CARD filaments, this bridge consists of two residues Gln185 and Tyr187, which extend from the Type IIb surface and interact with Ala168 and Asn170 on the Type IIa surface (Fig.…”

Section: Resultsmentioning

confidence: 47%

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Gong

Robinson

et al. 2021

Nat Commun

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Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.

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Section: Resultsmentioning

confidence: 47%

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Gong

Robinson

et al. 2021

Nat Commun

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“…3E). It is important to note that the very high fold induction in the case of CARD9 is mostly due to the very low basal activation of CARD9 compared to the other CARD‐CC proteins, which could reflect an additional layer of CARD9 autoinhibition [68]. The unequal expression of different PKC isoforms makes it difficult to precisely compare the potency of different PKCs to activate a given CARD‐CC.…”

Section: Resultsmentioning

confidence: 99%

Defining the combinatorial space of PKC::CARD‐CC signal transduction nodes

et al. 2020

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CARD‐CC/BCL10/MALT1 signaling complexes are activated by PKC‐mediated phosphorylation in response to specific upstream signals, leading to NF‐κB‐dependent gene expression. The caspase activation and recruitment domain (CARD)‐coiled‐coil domain (CC) family consists of four members and the PKC family of 9 members (subdivided in conventional, novel, and atypical subclasses). Here, we investigate the possible functional interactions between each specific PKC and CARD‐CC family member.

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“…4a-b to Fig. 3c-d), which had not been highlighted by previous analyses 20,27,[29][30][31][32][33][34][35] . In ASC-CARD filaments, this bridge consists of two residues Gln185 and Tyr187, which extend from the Type IIb surface and interact with Ala168 and Asn170 on the Type IIa surface ( Fig.…”

Section: Structural Basis For the Distinct Downstream Card Preferencementioning

confidence: 50%

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Gong

Robinson²,

et al. 2020

Preprint

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Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related NLR proteins, NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, the molecular mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIIND UPA -CARD) of NLRP1 and CARD8 self-oligomerize to trigger the assembly of distinct inflammasome complexes. Recombinant FIIND UPA -CARD of NLRP1 forms a two-layered filament, with an inner core composed of oligomerized CARD domains and the outer layer consisting of FIIND UPA rings.Biochemically, oligomerized NLRP1-CARD is sufficient to drive ASC speck formation in cultured human cells via filament formation-a process that is greatly enhanced by NLRP1-FIIND UPA , which forms ring-like oligomers in vitro. In addition, we report the cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments at 3.7 Å, which uncovers unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide unique structural insight into the mechanisms of activation for human NLRP1 and CARD8, uncovering an unexpected level of specificity in inflammasome signaling mediated by heterotypic CARD domain interactions.

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Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation

Cited by 36 publications

References 73 publications

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Defining the combinatorial space of PKC::CARD‐CC signal transduction nodes

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

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