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The PYRIN Domain-Only Protein POP1 Inhibits Inflammasome

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The PYRIN Domain-Only Protein POP1 Inhibits Inflammasome Article The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease Graphical Abstract Authors Lucia de Almeida, Sonal Khare, Alexander V. Misharin, ..., Hal M. Hoffman, Andrea Dorfleutner, Christian Stehlik Correspondence a-dorfl[email protected] (A.D.), [email protected] (C.S.) In Brief Inflammatory responses need to be tightly controlled to maintain homeostasis. Stehlik and colleagues demonstrate that the PYRIN domain-only protein POP1 inhibits ASC-containing inflammasome assembly and consequently caspase-1 activation, IL-1b and IL-18 release, pyroptosis, and the release of ASC particles in macrophages. Importantly, transgenic POP1 expression protects mice from systemic inflammation. Highlights d POP1 inhibits inflammasome-mediated responses to PAMPs and DAMPs d POP1 prevents IL-1b and IL-18 release and pyroptosis d POP1 prevents ASC danger particle-mediated response propagation to bystander cells d Transgenic POP1 expression protects mice from systemic inflammation de Almeida et al., 2015, Immunity 43, 264–276 August 18, 2015 ª2015 Elsevier Inc. http://dx.doi.org/10.1016/j.immuni.2015.07.018 Immunity Article The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease Lucia de Almeida,1 Sonal Khare,1 Alexander V. Misharin,1 Rajul Patel,1 Rojo A. Ratsimandresy,1 Melissa C. Wallin,1 Harris Perlman,1 David R. Greaves,2 Hal M. Hoffman,3 Andrea Dorfleutner,1,* and Christian Stehlik1,4,* 1Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA 2Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK 3Division of Rheumatology, Allergy, and Immunology, Department of Pediatrics, School of Medicine, University of California at San Diego (UCSD) and San Diego Branch, Ludwig Institute of Cancer Research, La Jolla, CA 92093, USA 4Robert H. Lurie Comprehensive Cancer Center, Interdepartmental Immunobiology Center and Skin Disease Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA *Correspondence: a-dorfl[email protected] (A.D.), [email protected] (C.S.) http://dx.doi.org/10.1016/j.immuni.2015.07.018 SUMMARY (ALR) and Nod-like receptor (NLR) families facilitate the activa- tion of the pro-inflammatory caspase-1 within large macro- In response to infections and tissue damage, ASC- molecular protein complexes in macrophages, referred to as containing inflammasome protein complexes are inflammasomes. Inflammasomes promote the proteolytic matu- assembled that promote caspase-1 activation, ration and release of the leaderless pro-inflammatory cytokines IL-1b and IL-18 processing and release, pyroptosis, interleukin (IL)-1b and IL-18 and the induction of pyroptotic cell a and the release of ASC particles. However, excessive death, which causes the release of IL-1 and HMGB1 (Martinon or persistent activation of the inflammasome causes et al., 2002; Khare et al., 2010; Wen et al., 2013). Inflammasomes are composed of a sensory PRR, which is linked to caspase-1 via inflammatory diseases. Therefore, a well-balanced the adaptor protein ASC (Srinivasula et al., 2002; Stehlik et al., inflammasome response is crucial for the mainte- 2003a; Martinon et al., 2002). This complex exhibits specific nance of homeostasis. We show that the PYD-only protein-protein interactions, which are mediated by homotypic protein POP1 inhibited ASC-dependent inflamma- PYRIN domain (PYD) interactions between PRRs and ASC and some assembly by preventing inflammasome nucle- by homotypic caspase recruitment domain (CARD) interactions ation, and consequently interfered with caspase-1 between ASC and pro-caspase-1. Within this protein complex, activation, IL-1b and IL-18 release, pyroptosis, and pro-caspase-1 is activated by induced proximity-mediated olig- the release of ASC particles. There is no mouse omerization (Martinon et al., 2002; Lu et al., 2014). The underlying ortholog for POP1, but transgenic expression of assembly mechanism of this ternary complex has recently been human POP1 in monocytes, macrophages, and delineated and indicates that PRR activation triggers prion-like, dendritic cells protected mice from systemic inflam- self-perpetuating ASC polymerization into filaments, which is initialized by PRR-induced ASCPYD nucleation (Cai et al., 2014; mation triggered by molecular PAMPs, inflamma- Lu et al., 2014; Franklin et al., 2014; Dorfleutner et al., 2015). some component NLRP3 mutation, and ASC danger PRRs localize to the end of the hollow ASC filaments and allow particles. POP1 expression was regulated by TLR efficient self-propagation of the ASCPYD, whereby the ASCCARD and IL-1R signaling, and we propose that POP1 pro- is flexibly linked to the outside of the filaments, allowing recruit- vides a regulatory feedback loop that shuts down ment and clustering of pro-caspase-1 (Lu et al., 2014). Eventu- excessive inflammatory responses and thereby pre- ally, these filaments can assemble into a spherical structure, vents systemic inflammation. where caspase-1 is placed in the hollow core (Man et al., 2014). Thus, the PYD is essential for inflammasome assembly after activation of NLRP3 and other PYD-containing PRRs, and INTRODUCTION disassembly of this ternary signaling complex is required for its termination. NLRP3 is one of the best-studied inflammasome- Inflammation is an essential and tightly controlled process activating PRRs and the NLRP3 inflammasome is regulated by initiated by the innate immune system in response to infection a two-step mechanism, referred to as priming and activation and tissue damage and is responsible for pathogen clearance, (Khare et al., 2010). After priming with LPS or other NF-kB- wound healing, and restoring homeostasis. It is triggered by inducing signals, NLRP3 is activated in a second step by a the sensing of pathogen-associated molecular patterns (PAMPs) wide variety of PAMPs that cause potassium (K+) efflux, or damage-associated molecular patterns (DAMPs or danger including exogenous ATP, nigericin, and uric acid crystals, as signals) by germline-encoded pattern recognition receptors well as environmental and endogenous mediators released (PRRs). Particularly, cytosolic PRRs of the AIM2-like receptor in response to stress and tissue damage (Khare et al., 2010; 264 Immunity 43, 264–276, August 18, 2015 ª2015 Elsevier Inc. Mun˜ oz-Planillo et al., 2013). Besides inflammasome-linked two different shRNAs causing elevated IL-1b release in response cytokines, oligomeric ASC particles are also released and to LPS and POP1 silencing) was confirmed by qPCR (Figure 1A). phagocytized by neighboring cells to perpetuate inflammasome Similarly, siRNA-mediated silencing of POP1 in primary human responses (Franklin et al., 2014; Baroja-Mazo et al., 2014). Over- macrophages resulted in elevated IL-1b and IL-18, but not all, inflammasomes play an essential role in host defense. IL-6, release in response to LPS. POP1 silencing was again However, impaired inflammasome activation results in failure confirmed by qPCR (Figure 1B). Conversely, THP-1 cells stably to restrict colitogenic microbiota species and subsequently expressing GFP-POP1 displayed diminished IL-1b secretion in promotes metabolic dysfunction. In contrast, constitutive inflam- response to LPS and also in response to non-canonical inflam- masome activation through disease-associated mutations in masome activation with LPS transfection or cytosolic delivery NLRP3 promotes excessive IL-1b release and causes inflamma- of LPS with cholera toxin subunit B (CTB) (Figure 1C). Cytokine tory diseases, including Cryopyrinopathies (or Cryopyrin-associ- release after non-canonical inflammasome activation requires ated periodic syndromes; CAPS) (Henao-Mejia et al., 2012; NLRP3. Consistently, POP1 blocked IL-1b release after NLRP3 Hoffman and Brydges, 2011). Therefore, a controlled and well- inflammasome activation with nigericin, calcium pyrophosphate balanced inflammasome response is essential for maintaining dehydrate (CPPD) crystals, or K+ depletion. Furthermore, POP1 homeostasis. However, the molecular mechanisms regulating blocked IL-1b release after AIM2 and NLRC4 activation with assembly and disassembly of inflammasomes are largely un- poly(dA:dT) or flagellin transfection, respectively (Figure 1D), known. We discovered a family of PYD-only proteins (POPs) and POP1 expression was confirmed by qPCR (Figure 1E). that are encoded in humans but not in mice (Stehlik and Dorfleut- Hence, POP1 inhibits inflammasome-dependent cytokine ner, 2007; Khare et al., 2014; Stehlik et al., 2003b; Dorfleutner release. Comparable results were also obtained for myc-tagged et al., 2007a, 2007b; Bedoya et al., 2007; Johnston et al., POP1, thus establishing that the GFP tag does not affect the 2005). We recently demonstrated that POP3 functions as a spe- function of POP1 (Figure S1A). cific inhibitor for ALR inflammasomes (Khare et al., 2014). POP3 binds to the PYD of ALRs, but not to ASC or NLRs, and thereby POP1 Impairs ASCPYD Nucleation and Caspase-1 prevents ALR interactions with the inflammasome adaptor ASC. Activation in Human Macrophages However, the function of endogenous POP1 (PYD-containing 1, Caspase-1 activation in canonical inflammasomes of macro- PYDC1) has not yet been established. POP1 is highly similar to phages is required for IL-1b and IL-18 release and for pyroptosis. the PYD of ASC and in vitro overexpression experiments showed Therefore, we determined caspase-1 activity in the presence that POP1 interacts
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