title: The molecular mechanisms of signaling by cooperative assembly formation in innate immunity pathways.
abstract: The innate immune system is the first line of defense against infection and responses are initiated by pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs). PRRs also detect endogenous danger-associated molecular patterns (DAMPs) that are released by damaged or dying cells. The major PRRs include the Toll-like receptor (TLR) family members, the nucleotide binding and oligomerization domain, leucine-rich repeat containing (NLR) family, the PYHIN (ALR) family, the RIG-1-like receptors (RLRs), C-type lectin receptors (CLRs) and the oligoadenylate synthase (OAS)-like receptors and the related protein cyclic GMP-AMP synthase (cGAS). The different PRRs activate specific signaling pathways to collectively elicit responses including the induction of cytokine expression, processing of pro-inflammatory cytokines and cell-death responses. These responses control a pathogenic infection, initiate tissue repair and stimulate the adaptive immune system. A central theme of many innate immune signaling pathways is the clustering of activated PRRs followed by sequential recruitment and oligomerization of adaptors and downstream effector enzymes, to form higher-order arrangements that amplify the response and provide a scaffold for proximity-induced activation of the effector enzymes. Underlying the formation of these complexes are co-operative assembly mechanisms, whereby association of preceding components increases the affinity for downstream components. This ensures a rapid immune response to a low-level stimulus. Structural and biochemical studies have given key insights into the assembly of these complexes. Here we review the current understanding of assembly of immune signaling complexes, including inflammasomes initiated by NLR and PYHIN receptors, the myddosomes initiated by TLRs, and the MAVS CARD filament initiated by RIG-1. We highlight the co-operative assembly mechanisms during assembly of each of these complexes.
authors.affiliation: School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Parimala R
authors.initials: PR
authors.lastname: Vajjhala
authors.affiliation: School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia; Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ve
authors.affiliation: School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia; School of Biological Sciences, Flinders University, Adelaide, SA 5001, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Bentham
authors.affiliation: School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Katryn J
authors.initials: KJ
authors.lastname: Stacey
authors.affiliation: School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: b.kobe@uq.edu.au.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Kobe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000071476:Caspase Activation and Recruitment Domain; D000071457:DEAD Box Protein 58 / Q000378:metabolism; D005658:Fungi / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology*; D000070576:NLR Proteins / Q000737:chemistry / Q000378:metabolism*; D010944:Plants / Q000276:immunology; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D058847:Inflammasomes; C505371:MAVS protein, human; D000070576:NLR Proteins; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; D051193:Toll-Like Receptors; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58
keywords: Higher-order assembly signaling; Inflammasome; Leucine-rich repeat-containing/nucleotide and oligomerization domain-like receptor (NLR); Nucleotide binding and oligomerization domain; RIG-1-like receptor (RLR); Signaling by co-operative assembly formation (SCAF); Toll-like receptor (TLR)