SMOCs: supramolecular organizing centres that control innate immunity - PubMed (original) (raw)

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SMOCs: supramolecular organizing centres that control innate immunity

Jonathan C Kagan et al. Nat Rev Immunol. 2014 Dec.

Abstract

The diverse receptor families of the innate immune system activate signal transduction pathways that are important for host defence, but common themes to explain the operation of these pathways remain undefined. In this Opinion article, we propose--on the basis of recent structural and cell biological studies--the concept of supramolecular organizing centres (SMOCs) as location-specific higher-order signalling complexes in which increased local concentrations of signalling components promote the intrinsically weak allosteric interactions that are required for enzyme activation. We suggest that SMOCs are assembled on various membrane-bound organelles or other intracellular sites, which may assist signal amplification to reach a response threshold and potentially define the specificity of cellular responses that are induced in response to infectious and non-infectious insults.

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Figures

Figure 1

Figure 1. SMOC formation for TLRs, RLRs and NLRs

Depicted are the best-studied supramolecular organizing centres (SMOCs), including the ligands and regulatory proteins that promote their assembly, and the downstream biological activities induced by these protein complexes. The figure does not show the exact stoichiometry of the protein components in each signalling complex. Binding of lipopolysaccharide (not shown) activates Toll-like receptor 4 (TLR4), leading to assembly of a Myddosome on the plasma membrane. By contrast, unmethylated CpG-containing DNA oligonucleotides (not shown) promote TLR9 to assemble an endosomal Myddosome. The TLR-specific sorting adaptor Toll/IL-1R domain-containing adaptor protein (TIRAP) facilitates Myddosome assembly. TIRAP has an amino-terminal lipid-binding domain that interacts promiscuously with acidic phosphoinositides and phosphatidylserine. For example, TIRAP is depicted as binding phosphatidylinositol-3-phosphate (PtdIns3P) and phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) on the endosomal membrane and the plasma membrane, respectively. Binding of cardiolipin, which translocates to the outer mitochondrial membrane upon mitochondrial dysfunction, relieves the autoinhibited state of NOD-, LRR- and pyrin domain-containing 3 (NLRP3). This in turn may promote NLRP3 inflammasome assembly through downstream pyrin domain (PYD)–PYD and caspase activation and recruitment domain (CARD)–CARD interactions. Activation of RIG-I-like receptors — retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5) — leads to the formation of higher-order oligomers of mitochondrial antiviral signalling protein (MAVS). IFN, interferon; IκBα, NF-κB inhibitor-α; IL, interleukin; IRAK, IL-1 receptor-associated kinase; IRF, IFN-regulatory factor; LRR, leucine-rich repeat; MYD88, myeloid differentiation primary response protein 88; NOD, nucleotide-binding oligomerization domain; NF-κB, nuclear factor-κB; TAB1, TAK1-binding protein 1; TAK1, TGFβ-associated kinase 1; TRAF, tumour necrosis factor receptor-associated factor.

Figure 2

Figure 2. Structures of SMOCs that are formed by the mechanism of nucleated polymerization

a | A ribbon diagram of the electron cryomicroscopic structure of polymerized ASC pyrin domain (ASCPYD) filaments in inflammasomes (shown in red, purple and orange for each of the three helical strands), in complex with polymerized absent in melanoma 2 PYD (AIM2PYD) filaments (shown in blue) formed upon double-stranded DNA (dsDNA) stimulation. b | A ribbon diagram of the electron cryomicroscopic structure of polymerized mitochondrial antiviral signalling protein caspase activation and recruitment domain (MAVSCARD) in the RIG-I-like receptor (RLR) pathway (shown in purple), in complex with a retinoic acid-inducible gene I (RIG-I) double CARD (RIG-I2CARD) tetramer (shown in blue, cyan, green and yellow) upon viral RNA stimulation. c | Proposed mechanism of nucleated polymerization for the formation of ASCPYD and MAVSCARD SMOCs. Receptors (for example, AIM2 and RIG-I) are shown in red wedges for monomers and in red disks for oligomerized forms. Adaptors (for example, ASC and MAVS) are shown in blue wedges for monomers and in blue cylinders for filaments.

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