Cellular Pyrin Domain-Only Protein 2 Is a Candidate Regulator of Inflammasome Activation

Dorfleutner, Andrea; Bryan, Nicole B.; Talbott, Siera Jo; Funya, Kristin N.; Rellick, Stephanie L.; Reed, John C.; Shi, Xianglin; Rojanasakul, Yon; Flynn, Daniel C.; Stehlik, Christian

doi:10.1128/iai.01315-06

Cited by 80 publications

(108 citation statements)

References 34 publications

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…One possible difference between the two systems is that pyrin domains have recently been identified as activating the inflammasome complexes by responding to changes in cytoskeletal dynamics, especially modification of Rho GTPases (42). However, THP-1 cells have pyrin-only proteins (POPs) that can finetune the activation of pyrin domain-containing Nod-like receptor (PYD-NLR) inflammasomes (43,44). These POPs are not present in mouse cells (45).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Inflammasome Activation by Vibrio cholerae Secreted Toxins Vary with Strain Biotype

et al. 2015

Self Cite

View full text Add to dashboard Cite

Activation of inflammasomes is an important aspect of innate immune responses to bacterial infection. Recent studies have linked Vibrio cholerae secreted toxins to inflammasome activation by using murine macrophages. To increase relevance to human infection, studies of inflammasome-dependent cytokine secretion were conducted with the human THP-1 monocytic cell line and corroborated in primary human peripheral blood mononuclear cells (PBMCs). Both El Tor and classical strains of V. cholerae activated ASC (apoptosis-associated speck-like protein-containing a CARD domain)-dependent release of interleukin-1␤ (IL-1␤) when cultured with human THP-1 cells, but the pattern of induction was distinct, depending on the repertoire of toxins the strains produced. El Tor biotype strains induced release of IL-1␤ dependent on NOD-like receptor family pyrin domain-containing 3 (NLRP3) and ASC due to the secreted pore-forming toxin hemolysin. Unlike in studies with mouse macrophages, the MARTX toxin did not contribute to IL-1␤ release from human monocytic cells. Classical biotype strains, which do not produce either hemolysin or the MARTX toxin, activated low-level IL-1␤ release that was induced by cholera toxin (CT) and dependent on ASC but independent of NLRP3 and pyroptosis. El Tor strains likewise showed increased IL-1␤ production dependent on CT when the hemolysin gene was deleted. In contrast to studies with murine macrophages, this phenotype was dependent on a catalytically active CT A subunit capable of inducing production of cyclic AMP and not on the B subunit. These studies demonstrate that the induction of the inflammasome in human THP-1 monocytes and in PBMCs by V. cholerae varies with the biotype and is mediated by both NLRP3-dependent and -independent pathways. V ibrio cholerae is the causative agent of the diarrheal disease cholera. The O1 serogroup, which is most associated with disease, is divided into two biotypes, classical and El Tor. Classical strains were responsible for the six cholera pandemics that occurred during the 19th century and the first half of the 20th century and are noted for their severe clinical presentation. In 1961, the El Tor strains emerged as the cause of the ongoing seventh pandemic, completely displacing the classical strains from the environment and as a cause of cholera in humans (1). These strains colonize the intestine more effectively and spread between hosts more efficiently but cause fewer deaths and significantly more asymptomatic colonization (2).The primary virulence factor for pandemic cholera strains is cholera toxin (CT), an ADP-ribosylating toxin that disables the G␣ s subunit, resulting in increased cyclic AMP (cAMP) production and secretion of fluid from enterocytes due to the opening of chloride channels. The toxin is composed of the catalytically active A (CTA) subunit associated with five CTB subunits that bind to surface GM 1 gangliosides, facilitating toxin endocytosis (3). In addition to enterotoxigenic activity, CT has also been demonstrated to have immunomodulat...

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanisms of Inflammasome Activation by Vibrio cholerae Secreted Toxins Vary with Strain Biotype

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Further support for this comes from the fact that poxviruses encode pyrin-only proteins (POPs), which inhibit inflammasome activation. Mammalian POPs were recently reported to inhibit inflammasome binding to the pyrin domains of either ASC (POP1 and -2) or AIM2 and IFI16 (POP3) (138)(139)(140), thus inhibiting the activation of these inflammasomes by DNA viruses (138). Many poxviruses encode POPs that share a high degree of similarity with mammalian POPs.…”

Section: Viral Evasion Of the Dna Sensing Machinerymentioning

confidence: 99%

Activation and Regulation of DNA-Driven Immune Responses

Paludan

2015

Microbiol Mol Biol Rev

108

View full text Add to dashboard Cite

SUMMARY The innate immune system provides early defense against infections and also plays a key role in monitoring alterations of homeostasis in the body. DNA is highly immunostimulatory, and recent advances in this field have led to the identification of the innate immune sensors responsible for the recognition of DNA as well as the downstream pathways that are activated. Moreover, information on how cells regulate DNA-driven immune responses to avoid excessive inflammation is now emerging. Finally, several reports have demonstrated how defects in DNA sensing, signaling, and regulation are associated with susceptibility to infections or inflammatory diseases in humans and model organisms. In this review, the current literature on DNA-stimulated innate immune activation is discussed, and important new questions facing this field are proposed.

show abstract

“…POP1 shows 64% identity to the PYD of ASC and interacts with ASC in a PYDdependent manner to displace other ASC-interacting proteins, thereby preventing ASC recruitment to NLRPs (30). A second POP (POP2) is also encoded in humans (32,33). POP2 shows a lesser degree of homology to the PYD of ASC but is very similar to the PYD of several NLRPs, in particular NALP2 (NLRP2) and NALP7 (NLRP7), where it shows 69 and 50% protein similarity, respectively.…”

Section: Pops As Modifiers Of Inflammasomesmentioning

confidence: 99%

COPs and POPs: Modulators of Inflammasome Activity

Stehlik

Dorfleutner

2007

The Journal of Immunology

Self Cite

115

106

View full text Add to dashboard Cite

Inflammasomes represent molecular platforms for the activation of inflammatory caspases and are essential for processing and secretion of the inflammatory cytokines IL-1β and IL-18. Multiple key proteins of inflammasomes contain caspase recruitment domains (CARDs) or pyrin domains (PYDs). Dissecting CARD- and PYD-mediated interactions substantially improved our understanding of the mechanisms by which these protein platforms are activated and emphasized their essential role during the inflammatory cytokine response. However, their precise regulation is still poorly understood. A family of small proteins that are composed of either a CARD or a PYD only emerged as important inflammasome regulators. These CARD-only proteins (COPs) and PYD-only proteins (POPs) function as endogenous dominant negative proteins that modulate the activity of inflammasomes in response to pathogen infection and tissue destruction. In this review we will summarize the most recent advances in the regulation of inflammasomes and highlight their importance for immunity and inflammatory disease.

show abstract

Cellular Pyrin Domain-Only Protein 2 Is a Candidate Regulator of Inflammasome Activation

Cited by 80 publications

References 34 publications

Mechanisms of Inflammasome Activation by Vibrio cholerae Secreted Toxins Vary with Strain Biotype

Mechanisms of Inflammasome Activation by Vibrio cholerae Secreted Toxins Vary with Strain Biotype

Activation and Regulation of DNA-Driven Immune Responses

COPs and POPs: Modulators of Inflammasome Activity

Contact Info

Product

Resources

About