The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation

Ratsimandresy, Rojo A.; Chu, Lan H.; Khare, Shruti; Almeida, Lúcia de; Gangopadhyay, Anu; Indramohan, Mohanalaxmi; Misharin, Alexander V.; Greaves, David R.; Perlman, Harris; Dorfleutner, Andrea; Stehlik, Christian

doi:10.1038/ncomms15556

Cited by 52 publications

(93 citation statements)

References 69 publications

(142 reference statements)

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“…Further, it remains unclear why more neutrophils are not evident in blood or lymph nodes. Concurrent with this report, mice transgenic for CD68 promoter-drive POP2 targeting constitutive macrophage-lineage expression of POP2 have also been described56. The distinctions between constitutive macrophage-lineage specific and endogenously regulated POP2 expression are likely to prove useful in exploring the functions of POP2.…”

Section: Discussionmentioning

confidence: 82%

Pyrin-only protein 2 limits inflammation but improves protection against bacteria

et al. 2017

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Pyrin domain-only proteins (POPs) are recently evolved, primate-specific proteins demonstrated in vitro as negative regulators of inflammatory responses. However, their in vivo function is not understood. Of the four known POPs, only POP2 is reported to regulate NF-κB-dependent transcription and multiple inflammasomes. Here we use a transgenic mouse-expressing POP2 controlled by its endogenous human promotor to study the immunological functions of POP2. Despite having significantly reduced inflammatory cytokine responses to LPS and bacterial infection, POP2 transgenic mice are more resistant to bacterial infection than wild-type mice. In a pulmonary tularaemia model, POP2 enhances IFN-γ production, modulates neutrophil numbers, improves macrophage functions, increases bacterial control and diminishes lung pathology. Thus, unlike other POPs thought to diminish innate protection, POP2 reduces detrimental inflammation while preserving and enhancing protective immunity. Our findings suggest that POP2 acts as a high-order regulator balancing cellular function and inflammation with broad implications for inflammation-associated diseases and therapeutic intervention.

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Section: Discussionmentioning

confidence: 82%

Pyrin-only protein 2 limits inflammation but improves protection against bacteria

et al. 2017

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“…Finally, another indication that Death Domains operate differently at the atomic and molecular levels despite sharing a common fold is the participation of three interacting regions in ASC CARD self-association, compared with a prominent role of the type I interaction for ASC PYD oligomerization (14). Information on the subtle differences in Death Domain interactions is critical to understand inflammasome inhibition and regulation using decoy proteins, such as the Pyrin-or CARD-only proteins POPs and COPs (33,34), that could be used as pharmacological targets.…”

Section: Asc Domains Pyd and Card Form Asc Filament Corementioning

confidence: 99%

The inflammasome adapter ASC assembles into filaments with integral participation of its two Death Domains, PYD and CARD

Nambayan

Sandin

Quint

et al. 2019

Journal of Biological Chemistry

105

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The inflammasome is a multiprotein complex necessary for the onset of inflammation. The adapter protein ASC assembles inflammasome components by acting as a molecular glue between danger-signal sensors and procaspase-1. The assembly is mediated by ASC self-association and protein interactions via its two Death Domains, PYD and CARD. Truncated versions of ASC have been shown to form filaments, but information on the filaments formed by full-length ASC is needed to construct a meaningful model of inflammasome assembly. To gain insights into this system, we used a combination of transmission EM, NMR, and computational analysis to investigate intact ASC structures. We show that ASC forms ϳ6 -7-nm-wide filaments that stack laterally to form bundles. The structural characteristics and dimensions of the bundles indicate that both PYD and CARD are integral parts of the filament. A truncated version of ASC with only the CARD domain (ASC CARD ) forms different filaments (ϳ3-4-nm width), providing further evidence that both domains work in concert in filament assembly. Ring-shaped protein particles bound to pre-existing filaments match the size of ASC dimer structures generated by NMR-based protein docking, suggesting that the ASC dimer could be a basic building block for filament formation. Solution NMR binding studies identified the protein surfaces involved in the ASC CARD -ASC CARD interaction. These data provide new insights into the structural underpinnings of the inflammasome and should inform future efforts to interrogate this important biological system. Figure 13. Model for ASC-dependent inflammasome assembly based on TEM data. ASC dimer is shown as the minimal building block. The ASC filament shows two interacting sides, one for recruiting procaspase-1 CARD and the other for interaction with the PYD of NLR sensor proteins. ASC domains, PYD and CARD, form ASC filament core

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“…Whether ASC is available for recruitment can be regulated by its localization; IKKα was proposed to restrain ASC in the nucleus, and phosphorylation of S58 in the PYD of ASC by IKKi appears necessary to release IKKα from ASC in response to diverse inflammasome triggers and to allow its cytoplasmic localization . In primates, but not mice, the Pyrin‐only proteins Pop1 and Pop2 interact with the PYD of ASC and—when overexpressed—block the recruitment of ASC to NLRP3, and likely other sensors, thus preventing inflammasome assembly . Knockdown of endogenous POPs enhances inflammatory responses and likely lowers the threshold for activation.…”

Section: Assembly and Regulation Of Asc Specksmentioning

confidence: 99%

“…mice, the Pyrin-only proteins Pop1 and Pop2 interact with the PYD of ASC and-when overexpressed-block the recruitment of ASC to NLRP3, and likely other sensors, thus preventing inflammasome assembly 38,39. Knockdown of endogenous POPs enhances inflammatory responses and likely lowers the threshold for activation.…”

mentioning

confidence: 99%

The intra‐ and extracellular functions of ASC specks

Franklin

Latz

Schmidt

2017

Immunological Reviews

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Inflammasomes are the central signaling hubs of the inflammatory response. They process cytosolic evidence of infection, cell damage, or metabolic disturbances, and elicit a pro-inflammatory response mediated by members of the interleukin-1 family of cytokines and pyroptotoic cell death. On the molecular level, this is accomplished by the sensor-nucleated recruitment and oligomerization of the adapter protein ASC. Once a tunable threshold is reached, cooperative assembly of ASC into linear filaments and their condensation into macromolecular ASC specks promotes an all-or-none response. These structures are highly regulated and provide a unique signaling platform or compartment to control the activity of caspase-1 and likely other effectors. Emerging evidence indicates that ASC specks are also released from inflammasome-activated cells and accumulate in inflamed tissues, where they can continue to mature cytokines or be internalized by surrounding cells to further nucleate ASC specks in their cytosol. Little is known about the mechanisms governing ASC speck release, uptake, and endosomal escape, as well as its contribution to inflammation and disease. Here, we describe the different outcomes of inflammasome activation and discuss the potential function of extracellular ASC specks. We highlight gaps in our understanding of this central process of inflammation, which may have direct consequences on the modulation of host responses and chronic inflammation.

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The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation

Cited by 52 publications

References 69 publications

Pyrin-only protein 2 limits inflammation but improves protection against bacteria

Pyrin-only protein 2 limits inflammation but improves protection against bacteria

The inflammasome adapter ASC assembles into filaments with integral participation of its two Death Domains, PYD and CARD

The intra‐ and extracellular functions of ASC specks

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