An updated view on the structure and function of PYRIN domains

Chu, Lan H.; Gangopadhyay, Anu; Dorfleutner, Andrea; Stehlik, Christian

doi:10.1007/s10495-014-1065-1

Cited by 35 publications

(49 citation statements)

References 106 publications

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“…Binding of ASC to NLRP3 induces ASC PYD nucleation, which provides the oligomeric platform essential for caspase-1 activation (Cai et al, 2014; Lu et al, 2014). Therefore we hypothesized that POP1 prevents ASC PYD -NLRP3 PYD interactions, and thus ASC PYD nucleation (Chu et al, 2015). Indeed, the nigericin-induced interaction of NLRP3 and ASC was abolished in LPS-primed THP-1 GFP-POP1 cells, indicating that POP1 may prevent NLRP3-mediated ASC nucleation (Figure 2F).…”

Section: Resultsmentioning

confidence: 99%

The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease

et al. 2015

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SUMMARY In response to infections and tissue damage, ASC-containing inflammasome protein complexes are assembled that promote caspase-1 activation, IL-1β and IL-18 processing and release, pyroptosis, and the release of ASC particles. However, excessive or persistent activation of the inflammasome causes inflammatory diseases. Therefore, a well-balanced inflammasome response is crucial to maintain homeostasis. We show that the PYD-only protein POP1 inhibited ASC-dependent inflammasome assembly by preventing inflammasome nucleation, and consequently interfered with caspase-1 activation, IL-1β and IL-18 release, pyroptosis and the release of ASC particles. There is no mouse ortholog for the POP1 gene, but transgenic expression of human POP1 in monocytes, macrophages and dendritic cells protected mice from systemic inflammation triggered by molecular PAMPs, inflammasome component NLRP3 mutation and ASC danger particles. POP1 expression was regulated by TLR- and IL-1R–signalling, and we propose that POP1 provides a regulatory feedback loop that shuts down excessive inflammatory responses and thereby prevents systemic inflammation.

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Section: Resultsmentioning

confidence: 99%

The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease

et al. 2015

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“…Active caspase-1 is required for the proteolytic maturation and release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 (Kostura et al, 1989; Thornberry et al, 1992; Fantuzzi et al, 1999; Ghayur et al, 1997; Kuida et al, 1995; Li et al, 1995), induction of pyroptosis (Fink and Cookson, 2006) and the release of alarmins and danger signals, including IL-1α, HMGB1 and inflammasome particles (Baroja-Mazo et al, 2014; Franklin et al, 2014; Groß et al, 2012; Lamkanfi et al, 2010; Willingham et al, 2009). The mechanism for inflammasome assembly involves ASC nucleation and the subsequent self-perpetuating polymerization of ASC (Cai et al, 2014; Lu et al, 2014; Man et al, 2014; Chu et al, 2015). Consequently polymerized ASC nucleates caspase-1 polymerization, which results in its activation (Stehlik et al, 2003a,b; Srinivasula et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides

Radian

Khare

Chu

et al. 2015

Molecular Immunology

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Nucleotide-binding oligimerization domain (NOD)-like receptors (NLRs) are pattern recognition receptors (PRRs) involved in innate immune responses. NLRs encode a central nucleotide-binding domain (NBD) consisting of the NAIP, CIITA, HET-E and TP1 (NACHT) domain and the NACHT associated domain (NAD), which facilitates receptor oligomerization and downstream inflammasome signaling. The NBD contains highly conserved regions, known as Walker motifs, that are required for nucleotide binding and hydrolysis. The NLR containing a PYRIN domain (PYD) 7 (NLRP7) has been recently shown to assemble an ASC and caspase-1-containing high molecular weight inflammasome complex in response to microbial acylated lipopeptides and Staphylococcus aureus infection. However, the molecular mechanism responsible for NLRP7 inflammasome activation is still elusive. Here we demonstrate that the NBD of NLRP7 is an ATP binding domain and has ATPase activity. We further show that an intact nucleotide-binding Walker A motif is required for NBD-mediated nucleotide binding and hydrolysis, oligomerization, and NLRP7 inflammasome formation and activity. Accordingly, THP-1 cells expressing a mutated Walker A motif display defective NLRP7 inflammasome activation, interleukin (IL)-1β release and pyroptosis in response to acylated lipopeptides and S. aureus infection. Taken together, our results provide novel insights into the mechanism of NLRP7 inflammasome assembly.

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“…However, some structural differences between the subfamilies are observed within this common fold, including different charge distributions throughout the protein surface, diverse locations of hydrophobic patches, and the different lengths of certain ␣-helices. These differences are thought to lead to homotypic binding specificity (5), albeit certain heterotypic interactions are also known with proposed inhibitory roles in apoptotic and inflammatory pathways (1,6).…”

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ASC Pyrin Domain Self-associates and Binds NLRP3 Protein Using Equivalent Binding Interfaces

Oroz

Barrera-Vilarmau

Alfonso³

et al. 2016

Journal of Biological Chemistry

109

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Death domain superfamily members typically act as adaptors mediating in the assembly of supramolecular complexes with critical apoptosis and inflammation functions. These modular proteins consist of death domains, death effector domains, caspase recruitment domains, and pyrin domains (PYD). Despite the high structural similarity among them, only homotypic interactions participate in complex formation, suggesting that subtle factors differentiate each interaction type. It is thus critical to identify these factors as an essential step toward the understanding of the molecular basis of apoptosis and inflammation. The proteins apoptosis-associated speck-like protein containing a CARD (ASC) and NLRP3 play key roles in the regulation of apoptosis and inflammation through self-association and protein-protein interactions mediated by their PYDs. To better understand the molecular basis of their function, we have characterized ASC and NLRP3 PYD self-association and their intermolecular interaction by solution NMR spectroscopy and analytical ultracentrifugation. We found that ASC self-associates and binds NLRP3 PYD through equivalent protein regions, with higher binding affinity for the latter. These regions are located at opposite sides of the protein allowing multimeric complex formation previously shown in ASC PYD fibril assemblies. We show that NLRP3 PYD coexists in solution as a monomer and highly populated large-order oligomerized species. Despite this, we determined its monomeric three-dimensional solution structure by NMR and characterized its binding to ASC PYD. Using our novel structural data, we propose molecular models of ASC⅐ASC and ASC⅐NLRP3 PYD early supramolecular complexes, providing new insights into the molecular mechanisms of inflammasome and apoptosis signaling.Proteins of the death domain superfamily mediate in apoptotic, innate immunity, and inflammatory responses mainly through homotypic interactions (1). Specifically, they are responsible for the assembly of large signaling complexes in which kinases and caspases are activated (1-4). Despite the lack of sequence convergence within the superfamily, its members are characterized by adopting the so-called death fold, consisting of a globular fold with six ␣-helices arranged in a greek-key topology (1, 3). However, some structural differences between the subfamilies are observed within this common fold, including different charge distributions throughout the protein surface, diverse locations of hydrophobic patches, and the different lengths of certain ␣-helices. These differences are thought to lead to homotypic binding specificity (5), albeit certain heterotypic interactions are also known with proposed inhibitory roles in apoptotic and inflammatory pathways (1, 6).Detailed structural information on complexes formed by several members of the death domain superfamily is available. Some examples are the death domain interactions in the PIDDosome (7), the MyDDosome (8), the Fas⅐FADD (9, 10), and the Pelle⅐Tube death domain complexes (11), among others...

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An updated view on the structure and function of PYRIN domains

Cited by 35 publications

References 106 publications

The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease

The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease

ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides

ASC Pyrin Domain Self-associates and Binds NLRP3 Protein Using Equivalent Binding Interfaces

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