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Plant intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) detect pathogen effectors to trigger immune responses 1 . Indirect recognition of a pathogen effector by the dicotyledonous Arabidopsis thaliana coiled-coil domain containing NLR (CNL) ZAR1 induces the formation of a large hetero-oligomeric protein complex, termed the ZAR1 resistosome, which functions as a calcium channel required for ZAR1-mediated immunity 2 – 4 . Whether the resistosome and channel activities are conserved among plant CNLs remains unknown. Here we report the cryo-electron microscopy structure of the wheat CNL Sr35 5 in complex with the effector AvrSr35 6 of the wheat stem rust pathogen. Direct effector binding to the leucine-rich repeats of Sr35 results in the formation of a pentameric Sr35–AvrSr35 complex, which we term the Sr35 resistosome. Wheat Sr35 and Arabidopsis ZAR1 resistosomes bear striking structural similarities, including an arginine cluster in the leucine-rich repeats domain not previously recognized as conserved, which co-occurs and forms intramolecular interactions with the 'EDVID' motif in the coiled-coil domain. Electrophysiological measurements show that the Sr35 resistosome exhibits non-selective cation channel activity. These structural insights allowed us to generate new variants of closely related wheat and barley orphan NLRs that recognize AvrSr35. Our data support the evolutionary conservation of CNL resistosomes in plants and demonstrate proof of principle for structure-based engineering of NLRs for crop improvement. Evolutionary conservation of plant receptor structure allowed for generation of new variants of wheat and barley nucleotide-binding leucine-rich repeat receptors (NLRs) that recognize AvrSr35 of the wheat stem rust pathogen, supporting proof of principle for structure-based engineering of NLRs for crop improvement.

SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD⁺) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association–dependent NAD⁺ cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP⁺ (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD⁺ cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.

Plants utilise intracellular nucleotide-binding, leucine-rich repeat (NLR) immune receptors to detect pathogen effectors and activate local and systemic defence. NRG1 and ADR1 “helper” NLRs (RNLs) cooperate with enhanced disease susceptibility 1 (EDS1), senescence-associated gene 101 (SAG101) and phytoalexin-deficient 4 (PAD4) lipase-like proteins to mediate signalling from TIR domain NLR receptors (TNLs). The mechanism of RNL/EDS1 family protein cooperation is not understood. Here, we present genetic and molecular evidence for exclusive EDS1/SAG101/NRG1 and EDS1/PAD4/ADR1 co-functions in TNL immunity. Using immunoprecipitation and mass spectrometry, we show effector recognition-dependent interaction of NRG1 with EDS1 and SAG101, but not PAD4. An EDS1-SAG101 complex interacts with NRG1, and EDS1-PAD4 with ADR1, in an immune-activated state. NRG1 requires an intact nucleotide-binding P-loop motif, and EDS1 a functional EP domain and its partner SAG101, for induced association and immunity. Thus, two distinct modules (NRG1/EDS1/SAG101 and ADR1/EDS1/PAD4) mediate TNL receptor defence signalling. For defence, plants deploy nucleotide binding, leucine-rich repeat (NLR) immune receptors to detect pathogens that signal via modular networks of downstream proteins. Here the authors report rapid induced association of non-interchangeable signalling pathway module components after NLR activation.

Noroviruses (NoVs) are a leading cause of gastroenteritis globally, yet the host factors required for NoV infection are poorly understood. We identified host molecules that are essential for murine NoV (MNoV)-induced cell death, including CD300lf as a proteinaceous receptor. We found that CD300lf is essential for MNoV binding and replication in cell lines and primary cells. Additionally, Cd300lf-/- mice are resistant to MNoV infection. Expression of CD300lf in human cells breaks the species barrier that would otherwise restrict MNoV replication. The crystal structure of the CD300lf ectodomain reveals a potential ligand-binding cleft composed of residues that are critical for MNoV infection. Therefore, the presence of a proteinaceous receptor is the primary determinant of MNoV species tropism, whereas other components of cellular machinery required for NoV replication are conserved between humans and mice.

NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytoxicity thus providing an \"alternative self\" mechanism for MHC class I inhibition.

CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPα variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This \"one-two punch\" directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.

The prostaglandin D2 receptor 1 (DP1), a member of the prostanoid G protein-coupled receptor (GPCR) family, plays critical roles in allergic responses, sleep regulation, immune modulation, and vasodilation. Here, we present five high-resolution cryo-electron microscopy (cryo-EM) structures of the human DP1 receptor, including an apo structure, two inactive state structures bound to two different inverse agonists developed by ONO Pharmaceutical, and two active state structures in complex with the G s protein and bound to the endogenous agonist PGD2 and its selective derivative BW245C. Structural analysis, complemented by molecular dynamics simulations and site-directed mutagenesis, reveals key residues involved in ligand recognition and suggests a distinct activation mechanism for DP1, which lacks most of the conserved class A GPCR motifs. Notably, the unique residue K76 within the conserved sodium pocket acts as a major activation switch, while amphiphilic helix 8 adopts an unconventional orientation essential for receptor function. These findings offer valuable insights into the structure and function of prostanoid receptors and may facilitate the development of therapeutics targeting DP1. The prostaglandin DP1 receptor plays critical roles in allergic responses, sleep regulation, immune modulation, and vasodilation. Here, authors present atomic structures of DP1 in different states revealing molecular mechanisms of receptor inhibition and activation.

Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors activate cell death and confer disease resistance by unknown mechanisms. We demonstrate that plant Toll/interleukin-1 receptor (TIR) domains of NLRs are enzymes capable of degrading nicotinamide adenine dinucleotide in its oxidized form (NAD⁺). Both cell death induction and NAD⁺ cleavage activity of plant TIR domains require known self-association interfaces and a putative catalytic glutamic acid that is conserved in both bacterial TIR NAD⁺-cleaving enzymes (NADases) and the mammalian SARM1 (sterile alpha and TIR motif containing 1) NADase. We identify a variant of cyclic adenosine diphosphate ribose as a biomarker of TIR enzymatic activity. TIR enzymatic activity is induced by pathogen recognition and functions upstream of the genes enhanced disease susceptibility 1 (EDS1) and N requirement gene 1 (NRG1), which encode regulators required for TIR immune function. Thus, plant TIR-NLR receptors require NADase function to transduce recognition of pathogens into a cell death response.

Natural killer (NK) cells circulate through the blood, lymphatics and tissues, on patrol for the presence of transformed or pathogen-infected cells. As almost all NK cell receptors bind to host-encoded ligands, signals are constantly being transmitted into NK cells, whether they interact with normal or abnormal cells. The sophisticated repertoire of activating and inhibitory receptors that has evolved to regulate NK cell activity ensures that NK cells protect hosts against pathogens, yet prevents deleterious NK cell–driven autoimmune responses. Here I highlight recent advances in our understanding of the structural properties and signaling pathways of the inhibitory and activating NK cell receptors, with a particular focus on the ITAM-dependent activating receptors, the NKG2D-DAP10 receptor complexes and the CD244 receptor system.

Plants have evolved intracellular immune receptors to detect pathogen proteins known as effectors. How these immune receptors detect effectors remains poorly understood. Here we describe the structural basis for direct recognition of AVR-Pik, an effector from the rice blast pathogen, by the rice intracellular NLR immune receptor Pik. AVR-PikD binds a dimer of the Pikp-1 HMA integrated domain with nanomolar affinity. The crystal structure of the Pikp-HMA/AVR-PikD complex enabled design of mutations to alter protein interaction in yeast and in vitro, and perturb effector-mediated response both in a rice cultivar containing Pikp and upon expression of AVR-PikD and Pikp in the model plant Nicotiana benthamiana. These data reveal the molecular details of a recognition event, mediated by a novel integrated domain in an NLR, which initiates a plant immune response and resistance to rice blast disease. Such studies underpin novel opportunities for engineering disease resistance to plant pathogens in staple food crops. Plant diseases reduce harvests of the world's most important food crops including wheat, rice, potato, and corn. These diseases are important for both global food security and local subsistence farming. To fight these diseases, crops (like all plants) have an immune system that can detect the telltale molecules produced by disease-causing microbes (also known as pathogens) and mount a defence response to protect the plant. Nucleotide-binding, leucine-rich repeat receptors (or NLRs for short) are plant proteins that survey the inside of plant cells looking for these telltale molecules. These receptors have played a central role in efforts to breed disease resistance into crop plants for decades, but little is known about how they work. Maqbool, Saitoh et al. have now used a range of biochemical, structural biology and activity-based assays to study how one NLR from rice directly interacts with a molecule from the rice blast fungus. This fungus causes the most important disease of rice (called rice blast), and the fungal molecule in question is also known as an ‘effector’ protein. A technique called X-ray crystallography was used to reveal the three-dimensional structure of the effector bound to part of the NLR called the ‘integrated HMA domain’. Biochemical techniques were then used to measure how strongly the effector (and other related effectors) interacted with this domain of the NLR. These results, combined with a close examination of the three-dimensional structure, allowed a set of changes to be made to the effector that stopped it interacting with the NLR protein domain in the laboratory. Maqbool, Saitoh et al. then performed experiments in rice plants and showed that changes to the effector that stopped it interacting with the NLR domain also stopped the effector from triggering a defence response in plants. Similar results were also obtained in experiments that used the model plant Nicotiana benthamiana. In the middle of the 20th century, an American plant pathologist called Harold Henry Flor proposed that the outcomes of interactions between plants and disease-causing microbes were based on interactions between specific biological molecules. The findings of Maqbool, Saitoh et al. provide a new structural basis for this model. A detailed picture of these molecular interactions will allow researchers to engineer tailored NLRs that detect a wider range of pathogen molecules. In the future such an approach could contribute to efforts to protect the world's most important crops from plant diseases.