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

Periasamy, Sivakumar; Porter, Kristen A.; Atianand, Maninjay K.; Le, Hongnga T.; Earley, Sarah; Duffy, Ellen B.; Haller, Matthew C.; Chin, Heather; Harton, Jonathan A.

doi:10.1038/ncomms15564

Cited by 18 publications

(41 citation statements)

References 76 publications

(130 reference statements)

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“…In the same issue, Periasamy et al 62. used a similar approach to determine the in vivo role of POP2 by generating POP2 TG mice under the human POP2 promoter and came to a comparable conclusion that inducible POP2 expression prevented ASC-containing inflammasome-dependent- and inflammasome-independent pro-inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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Inflammasomes are protein platforms linking recognition of microbe, pathogen-associated and damage-associated molecular patterns by cytosolic sensory proteins to caspase-1 activation. Caspase-1 promotes pyroptotic cell death and the maturation and secretion of interleukin (IL)-1β and IL-18, which trigger inflammatory responses to clear infections and initiate wound-healing; however, excessive responses cause inflammatory disease. Inflammasome assembly requires the PYRIN domain (PYD)-containing adaptor ASC, and depends on PYD–PYD interactions. Here we show that the PYD-only protein POP2 inhibits inflammasome assembly by binding to ASC and interfering with the recruitment of ASC to upstream sensors, which prevents caspase-1 activation and cytokine release. POP2 also impairs macrophage priming by inhibiting the activation of non-canonical IκB kinase ɛ and IκBα, and consequently protects from excessive inflammation and acute shock in vivo. Our findings advance our understanding of the complex regulatory mechanisms that maintain a balanced inflammatory response and highlight important differences between individual POP members.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…NLRP7-PYD-based homology modelling suggested α helices 1 and 4 form a negatively charged surface, which may enable interaction with the positive surface patch of NLRP-PYDs and ASC-PYD, but a positively charged surface is absent in POP2. Similar to POP1, also POP2 expression is upregulated by inflammatory stimuli, and POP2 also co-localizes with ASC and regulates inflammasome assembly and downstream responses, but regulates also activation of NF-κB [150][151][152][153][154]. These two activities can be separated, as α helix 1 is crucial for regulating NF-κB, while the acidic residues E6, D8 and E16 are only essential for inhibiting canonical inflammasomes, but are not required for NF-κB inhibition [152].…”

Section: Pyd-only Proteinmentioning

confidence: 99%

An Update on CARD Only Proteins (COPs) and PYD Only Proteins (POPs) as Inflammasome Regulators

Devi

Stehlik

Dorfleutner

2020

IJMS

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Inflammasomes are protein scaffolds required for the activation of caspase-1 and the subsequent release of interleukin (IL)-1β, IL-18, and danger signals, as well as the induction of pyroptotic cell death to restore homeostasis following infection and sterile tissue damage. However, excessive inflammasome activation also causes detrimental inflammatory disease. Therefore, extensive control mechanisms are necessary to prevent improper inflammasome responses and inflammatory disease. Inflammasomes are assembled by sequential nucleated polymerization of Pyrin domain (PYD) and caspase recruitment domain (CARD)-containing inflammasome components. Once polymerization is nucleated, this process proceeds in a self-perpetuating manner and represents a point of no return. Therefore, regulation of this key step is crucial for a controlled inflammasome response. Here, we provide an update on two single domain protein families containing either a PYD or a CARD, the PYD-only proteins (POPs) and CARD-only proteins (COPs), respectively. Their structure allows them to occupy and block access to key protein–protein interaction domains necessary for inflammasome assembly, thereby regulating the threshold of these nucleated polymerization events, and consequently, the inflammatory host response.

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“…Inflammasome assembly requires the adaptor ASC that contains PYD and depends on the interaction between PYD-PYD. Interestingly, many studies have now demonstrated that POP2 (PYRIN domain only protein 2) blocks the recruitment of ASC to upstream sensors by binding to ASC, thereby preventing caspase-1 activation and cytokine release, blocking the NF-κB signaling pathway, and inhibiting inflammasome assembly (Periasamy et al, 2017;Ratsimandresy et al, 2017). Thus, we speculate that exogenous administration of "pyrinonly" proteins might affect PYD-protein interactions, which in turn modulate the NF-κB signaling pathway and alleviate the inflammatory response.…”

Section: Introductionmentioning

confidence: 90%

Recombinant Pyrin Domain Protein Attenuates Airway Inflammation and Alleviates Epithelial-Mesenchymal Transition by Inhibiting Crosstalk Between TGFβ1 and Notch1 Signaling in Chronic Asthmatic Mice

Wang

Piao

et al. 2020

Front. Physiol.

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This article aims to investigate the effects of recombinant pyrin domain (RPYD) on airway inflammation and remodeling in mice with chronic asthma. The chronic asthma BALB/c mouse model was first sensitized by ovalbumin (OVA) and then challenged by OVA nebulization. RPYD or dexamethasone was given before OVA challenge. Our results showed that RPYD significantly inhibited the increase of total cell number, eosinophils, neutrophils and lymphocytes in bronchoalveolar lavage fluid (BALF) induced by OVA, and reduced the infiltration of inflammatory cells, the proliferation of goblet cells and collagen deposition. In addition, RPYD inhibited the mRNA and protein levels of α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β1, Jagged1, Notch1, Hes1 and Smad3, as well as Smad3 phosphorylation. TGFβ1 down-regulated the level of E-cadherin and promoted the expression of α-SMA, thus inducing epithelialmesenchymal transition (EMT) in bronchial epithelial cells. We found that RPYD reduced EMT by inhibiting TGFβ1/smad3 and Jagged1/Notch1 signaling pathways. Further overexpression of NICD showed that under the stimulation of TGFβ1, NICD enhanced the phosphorylated Smad3 and nuclear Smad3, accompanied by the increased expression of Notch1 target gene Hes1. In contrast, after treatment with smad3 siRNA, the expression of Hes1 was down regulated as the decrease of Smad3, which indicates that there is crosstalk between smad3 and NICD on Hes1 expression. In conclusion, RPYD reduces airway inflammation, improves airway remodeling and reduces EMT in chronic asthmatic mice by inhibiting the crosstalk between TGFβ1/smad3 and Jagged1/Notch1 signaling pathways.

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

Cited by 18 publications

References 76 publications

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

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

An Update on CARD Only Proteins (COPs) and PYD Only Proteins (POPs) as Inflammasome Regulators

Recombinant Pyrin Domain Protein Attenuates Airway Inflammation and Alleviates Epithelial-Mesenchymal Transition by Inhibiting Crosstalk Between TGFβ1 and Notch1 Signaling in Chronic Asthmatic Mice

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