Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

Huang, Menghang; Zhang, Xiaoxiao; Ann, Toh Gee; Gong, Qin; Wang, Jia; Han, Zhifu; Wu, Bin; Zhong, Franklin L.; Chai, Jijie

doi:10.1101/2020.08.13.250241

Cited by 4 publications

(1 citation statement)

References 44 publications

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“…In addition to participating in biological functions through enzymatic activity, DPP9 also participates in protein-protein interactions [34][35][36]. We found that DPP9 interacts with the learningand memory-related proteins Ppp1r9b, Rac1, Ppp2r1a, etc.…”

Section: Discussionmentioning

confidence: 86%

Hippocampal Dipeptidyl Peptidase 9 Bidirectionally Regulates Memory Via Synaptic Plasticity

Zhao,

Wang,

Guo

et al. 2023

Preprint

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Dipeptidyl Peptidase family members are known to modulate memory through peripheral substrates. However, the direct impact of this family on the central nervous system (CNS) remains underexplored. Dipeptidyl peptidase 9 (DPP9) has been extensively studied for its role in inflammation and cancer. Here, we found that DPP9 is relevant highly expressed in hippocampal neurons. Electrophysiological and behavioral experiments have shown that it plays a pivotal role in long-term potentiation and memory. Proteomics analysis identified differentially expressed proteins associated with memory retrieval regulated by DPP9. Further investigation revealed that DPP9 enzymatic activity is essential for memory retrieval. DPP9-interacting proteins are involved in the function of the dendritic spine and axon, and two memory- and axon-related genes, Tmp3 and Baiap2, were identified as potential targets for DPP9. Our findings suggest that DPP9 is a novel memory regulatory protein and provide new insights into memory molecular mechanisms.

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Section: Discussionmentioning

confidence: 86%

Hippocampal Dipeptidyl Peptidase 9 Bidirectionally Regulates Memory Via Synaptic Plasticity

Zhao,

Wang,

Guo

et al. 2023

Preprint

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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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Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes

Hollingsworth

David

et al. 2021

Nat Commun

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NLRP1 and CARD8 are related cytosolic sensors that upon activation form supramolecular signalling complexes known as canonical inflammasomes, resulting in caspase−1 activation, cytokine maturation and/or pyroptotic cell death. NLRP1 and CARD8 use their C-terminal (CT) fragments containing a caspase recruitment domain (CARD) and the UPA (conserved in UNC5, PIDD, and ankyrins) subdomain for self-oligomerization, which in turn form the platform to recruit the inflammasome adaptor ASC (apoptosis-associated speck-like protein containing a CARD) or caspase-1, respectively. Here, we report cryo-EM structures of NLRP1-CT and CARD8-CT assemblies, in which the respective CARDs form central helical filaments that are promoted by oligomerized, but flexibly linked, UPAs surrounding the filaments. Through biochemical and cellular approaches, we demonstrate that the UPA itself reduces the threshold needed for NLRP1-CT and CARD8-CT filament formation and signalling. Structural analyses provide insights on the mode of ASC recruitment by NLRP1-CT and the contrasting direct recruitment of caspase-1 by CARD8-CT. We also discover that subunits in the central NLRP1CARD filament dimerize with additional exterior CARDs, which roughly doubles its thickness and is unique among all known CARD filaments. Finally, we engineer and determine the structure of an ASCCARD–caspase-1CARD octamer, which suggests that ASC uses opposing surfaces for NLRP1, versus caspase-1, recruitment. Together these structures capture the architecture and specificity of the active NLRP1 and CARD8 inflammasomes in addition to key heteromeric CARD-CARD interactions governing inflammasome signalling.

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Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

Cited by 4 publications

References 44 publications

Hippocampal Dipeptidyl Peptidase 9 Bidirectionally Regulates Memory Via Synaptic Plasticity

Hippocampal Dipeptidyl Peptidase 9 Bidirectionally Regulates Memory Via Synaptic Plasticity

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

Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes

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