Abstract
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.
Highlights
Inflammasomes are protein platforms linking recognition of microbe, pathogen-associated and damage-associated molecular patterns by cytosolic sensory proteins to caspase-1 activation
The mechanism for canonical inflammasome complex assembly depends on specific protein–protein interactions, which are mediated by homotypic PYRIN domain (PYD) interactions between pattern recognition receptors (PRRs) and ASC, and by homotypic CARD interactions between ASC and pro-caspase-1
Reminiscent of POP1 and POP3, POP2 is expressed in CD68 þ macrophages in inflamed human lung tissue, as shown by immunohistochemistry using a custom-raised POP2 antibody, which we validated for specificity among POPs20 (Fig. 1a)
Summary
Inflammasomes are protein platforms linking recognition of microbe, pathogen-associated and damage-associated molecular patterns by cytosolic sensory proteins to caspase-1 activation. 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. The mechanism for canonical inflammasome complex assembly depends on specific protein–protein interactions, which are mediated by homotypic PYRIN domain (PYD) interactions between PRRs and ASC, and by homotypic CARD interactions between ASC and pro-caspase-1 We previously demonstrated that the monocyte/macrophagespecific expression of POP1 prevents ASC-dependent inflammasome responses by binding to ASC and thereby preventing ASC– PRR interactions, which ameliorates systemic inflammation and auto-inflammatory disease[13]. We report that human POP2 simultaneously blocks NLRP3 inflammasome priming and activation in a macrophagespecific transgenic mouse model, and thereby ameliorates pathogen- and damage signal-induced systemic inflammation in vivo. Our study provides insights into the complex molecular mechanisms that regulate inflammasome activation in humans to limit systemic inflammatory disease
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