J. Appl. Cryst.の発刊に際して

Plants are engaged in a continuous co-evolutionary struggle for dominance with their pathogens. The outcomes of these interactions are of particular importance to human activities, as they can have dramatic effects on agricultural systems. The recent convergence of molecular studies of plant immunity and pathogen infection strategies is revealing an integrated picture of the plant-pathogen interaction from the perspective of both organisms. Plants have an amazing capacity to recognize pathogens through strategies involving both conserved and variable pathogen elicitors, and pathogens manipulate the defence response through secretion of virulence effector molecules. These insights suggest novel biotechnological approaches to crop protection.

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Plant immunity: towards an integrated view of plant―pathogen interactions

The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1β and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.

https://www.um.es/biomybiotec/web/Seminarios/2009/papers/Pablo_Pelegrín_Annu%20Rev%20Immunol%202009%20Martinon-1.pdf

The Inflammasomes: Guardians of the Body

The lipopolysaccharide (LPS) of Gram negative bacteria is a well-known inducer of the innate immune response. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules. To understand the ligand specificity and receptor activation mechanism of the TLR4-MD-2-LPS complex we determined its crystal structure. LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically. LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2, forming a hydrophobic interaction with the conserved phenylalanines of TLR4. The F126 loop of MD-2 undergoes localized structural change and supports this core hydrophobic interface by making hydrophilic interactions with TLR4. Comparison with the structures of tetra-acylated antagonists bound to MD-2 indicates that two other lipid chains in LPS displace the phosphorylated glucosamine backbone by approximately 5 A towards the solvent area. This structural shift allows phosphate groups of LPS to contribute to receptor multimerization by forming ionic interactions with a cluster of positively charged residues in TLR4 and MD-2. The TLR4-MD-2-LPS structure illustrates the remarkable versatility of the ligand recognition mechanisms employed by the TLR family, which is essential for defence against diverse microbial infection.

The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex

Immunogenicity depends on two key factors: antigenicity and adjuvanticity. The presence of exogenous or mutated antigens explains why infected cells and malignant cells can initiate an adaptive immune response provided that the cells also emit adjuvant signals as a consequence of cellular stress and death. Several infectious pathogens have devised strategies to control cell death and limit the emission of danger signals from dying cells, thereby avoiding immune recognition. Similarly, cancer cells often escape immunosurveillance owing to defects in the molecular machinery that underlies the release of endogenous adjuvants. Here, we review current knowledge on the mechanisms that underlie the activation of immune responses against dying cells and their pathophysiological relevance.

Immunogenic cell death in cancer and infectious disease

The Toll family of class I transmembrane receptors recognizes and responds to diverse structures associated with pathogenic microorganisms. These receptors mediate initial responses in innate immunity and are required for the development of the adaptive immune response. Toll receptor signaling pathways are also implicated in serious autoimmune diseases such as endotoxic shock and thus are important therapeutic targets. In this review we discuss how microbial structures as different as nucleic acids and lipoproteins can be recognized by the extracellular domains of Toll receptors. We review recent evidence that the mechanism of signal transduction is complex and involves sequential changes in the conformation of the receptor induced by binding of the ligand. Finally, we assess the emerging area of cross talk in the Toll pathways. Recent work suggests that signaling through TLR4 in response to endotoxin is modified by inputs from at least two other pathways acting through beta2 integrins and protein kinase Cepsilon.

Structure and Function of Toll Receptors and Their Ligands

Signal transduction by the Toll-like receptors (TLRs) is central to host defence against many pathogenic microorganisms and also underlies a large burden of human disease. Thus, the mechanisms and regulation of signalling by TLRs are of considerable interest. In this Review, we discuss the molecular basis for the recognition of pathogen-associated molecular patterns, the nature of the protein complexes that mediate signalling, and the way in which signals are regulated and integrated at the level of allosteric assembly, post-translational modification and subcellular trafficking of the components of the signalling complexes. These fundamental molecular mechanisms determine whether the signalling output leads to a protective immune response or to serious pathologies such as sepsis. A detailed understanding of these processes at the molecular level provides a rational framework for the development of new drugs that can specifically target pathological rather than protective signalling in inflammatory and autoimmune disease.

Assembly and localization of Toll-like receptor signalling complexes

Lipopolysaccharide (LPS), which is produced by Gram-negative bacteria, is a powerful activator of innate immune responses. LPS binds to the proteins Toll-like receptor 4 (TLR4) and MD2 to activate pro-inflammatory signalling pathways. The TLR4-MD2 receptor complex is crucial for the host recognition of Gram-negative bacterial infection, and pathogens have devised many strategies to evade or manipulate TLR4-MD2 activity. The TLR4-MD2 signalling pathway is therefore potentially an important therapeutic target. This Progress article focuses on recent exciting data that have revealed the structural basis of TLR4-MD2 recognition of LPS.

The molecular basis of the host response to lipopolysaccharide

Members of the Toll family of single-pass transmembrane receptors are key mediators of innate immunity in both vertebrates and invertebrates. They respond to various pathogen-associated stimuli and transduce the complex signalling responses that are required for inflammation and for the subsequent development of adaptive immunity. Here, we propose a molecular mechanism for signalling by the Toll and Toll-like receptors that involves a series of protein conformational changes initiated by dimerization of their extracellular domains. The initial dimerization event, which is triggered by the interaction of the receptor with its ligand, might disrupt a pre-formed but non-functional dimer. Formation of a stable receptor-ligand complex then relieves constitutive autoinhibition, enabling receptor-receptor association of the extracellular juxtamembrane regions and cytoplasmic signalling domains. This activation process constitutes a tightly regulated, unidirectional molecular switch.

Toll-like receptors as molecular switches

https://www.cell.com/trends/immunology/pdf/S1471-4906(10)00173-0.pdf

Monique Gangloff

Papers

Structure and Function of Toll Receptors and Their Ligands

Assembly and localization of Toll-like receptor signalling complexes

The molecular basis of the host response to lipopolysaccharide

Toll-like receptors as molecular switches

What the Myddosome structure tells us about the initiation of innate immunity