The Experts below are selected from a list of 121416 Experts worldwide ranked by ideXlab platform
Bushra Husain - One of the best experts on this subject based on the ideXlab platform.
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A Platform for Extracellular Interactome Discovery Identifies Novel Functional Binding Partners for the Immune Receptors B7-H3/CD276 and PVR/CD155.
Molecular & cellular proteomics : MCP, 2019Co-Authors: Bushra Husain, Sree R. Ramani, Eugene Chiang, Isabelle Lehoux, Sairupa Paduchuri, Tia A Arena, Ashka Patel, Blair Wilson, Pamela Chan, Yvonne FrankeAbstract:Receptors expressed on the plasma membrane and their interacting partners critically regulate cellular communication during homeostasis and disease, and as such represent main therapeutic targets. Despite its importance for drug development, receptor-ligand proteomics has remained a daunting field, in part because of the challenges associated to the study of membrane-expressed proteins. Here, to enable sensitive detection of receptor-ligand interactions in high throughput, we implement a new platform, the Conditioned Media AlphaScreen, for interrogation of a library consisting of most single transmembrane human proteins. Using this method to study key Immune Receptors, we identify and further validate the interleukin receptor IL20RA as the first binding partner for the checkpoint inhibitor B7-H3. Further, KIR2DL5, a natural killer cell protein that had remained orphan, is uncovered as a functional binding partner for the poliovirus receptor (PVR). This interaction is characterized using orthogonal assays, which demonstrate that PVR specifically engages KIR2DL5 on natural killer cells leading to inhibition of cytotoxicity. Altogether, these results reveal unappreciated links between protein families that may importantly influence receptor-driven functions during disease. Applicable to any target of interest, this technology represents a versatile and powerful approach for elucidation of receptor-ligand interactomes, which is essential to understand basic aspects of the biology of the plasma membrane proteins and ultimately inform the development of novel therapeutic strategies.
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A Platform for Extracellular Interactome Discovery Identifies Novel Functional Binding Partners for the Immune Receptors B7-H3/CD276 and PVR/CD155
Annals of Oncology, 2019Co-Authors: Bushra Husain, Nadia Martinez-martinAbstract:Abstract Background Anti-tumor immunity is critically regulated by Immune checkpoints such as TIM-3, PD-1 or TIGIT. Notwithstanding the remarkable success of the antibody-mediated Immune checkpoint blockade in the clinics, many key Immune Receptors remain orphan or poorly characterized, hindering the development of novel therapeutics. This is partially due to technical challenges associated with the study of membrane-expressed proteins and identification of receptor binding partners. Here, we present a new technology for receptor-ligand discovery, which we apply to investigate interactions established by key inhibitory Immune Receptors. Methods A new platform was developed for high sensitivity receptor-ligand discovery in high throughput, the Conditioned Media Alpha Screen. Using this method, prominent Immune Receptors were screened for binding to a library consisting of ≈1,200 single transmembrane proteins in the human genome. The new interactions were confirmed using biophysical and cell-based methods for functional characterization of select receptor-ligand pairs. Results Using this technology Interleukin-20 receptor subunit alpha (IL20RA) was identified as the first counter-receptor for B7-H3. Furthermore, the natural killer cell receptor KIR2DL5A is identified as a new binding partner for PVR, an interaction that is fully validated using orthogonal methods and cellular assays. Here we show that KIR2DL5A engagement by PVR expressed on tumor cells results in reduced natural killer cell cytotoxicity. PVR deletion or treatment with an anti-KIR2DL5A antibody restored NK-mediated cytolysis of tumor cells. Additionally, competition assays show that PVR interacts with both TIGIT and KIR2DL5A on the cell surface, suggesting a previously unrecognized mechanism of action. Conclusion Here we developed a new platform for elucidation of secreted or membrane protein interactomes. The power of this technology is demonstrated by identification of new interactors for emerging therapeutic targets such as PVR or B7-H3. These results provide insights into Immune receptor biology and highlight potential new cellular targets, ultimately serving as a unique tool to inform therapeutic development. Legal entity responsible for the study The authors. Funding Genentech Inc. Disclosure All authors have declared no conflicts of interest.
Marco Trujillo - One of the best experts on this subject based on the ideXlab platform.
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Ubiquitin signalling: controlling the message of surface Immune Receptors.
The New phytologist, 2021Co-Authors: Marco TrujilloAbstract:Microbial attack is first detected by Immune Receptors located at the plasma membrane (PM). Their activation triggers a plethora of signalling cascades that culminate in the Immune response. Ubiquitin, and ubiquitin-like protein modifiers, play key roles in controlling signalling amplitude and intensity, as well as in buffering proteome imbalances caused by pathogen attack. Here I highlight some of the important advances in the field, which are starting to reveal an intertwined and complex signalling circuitry, which regulates cellular dynamics and protein degradation to maintain homeostasis.
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Regulation of plant Immune Receptors by ubiquitination
Frontiers in Plant Science, 2012Co-Authors: Giulia Furlan, Jörn Klinkenberg, Marco TrujilloAbstract:From pathogen perception and the activation of signal transduction cascades to the deployment of defense responses, protein ubiquitination plays a key role in the modulation of plant immunity. Ubiquitination is mediated by three enzymes, of which the E3 ubiquitin ligases, the substrate determinants, have been the major focus of attention. Accumulating evidence suggests that ubiquitination modulates signaling mediated by pattern recognition Receptors and is important for the accumulation of nucleotide-binding leucine-rich repeat type intracellular Immune sensors. Recent studies also indicate that ubiquitination directs vesicle trafficking, a function that has been clearly established for Immune signaling in animals. In this mini review, we discuss these and other recent advances and highlight important open questions.
Nadia Martinez-martin - One of the best experts on this subject based on the ideXlab platform.
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A Platform for Extracellular Interactome Discovery Identifies Novel Functional Binding Partners for the Immune Receptors B7-H3/CD276 and PVR/CD155
Annals of Oncology, 2019Co-Authors: Bushra Husain, Nadia Martinez-martinAbstract:Abstract Background Anti-tumor immunity is critically regulated by Immune checkpoints such as TIM-3, PD-1 or TIGIT. Notwithstanding the remarkable success of the antibody-mediated Immune checkpoint blockade in the clinics, many key Immune Receptors remain orphan or poorly characterized, hindering the development of novel therapeutics. This is partially due to technical challenges associated with the study of membrane-expressed proteins and identification of receptor binding partners. Here, we present a new technology for receptor-ligand discovery, which we apply to investigate interactions established by key inhibitory Immune Receptors. Methods A new platform was developed for high sensitivity receptor-ligand discovery in high throughput, the Conditioned Media Alpha Screen. Using this method, prominent Immune Receptors were screened for binding to a library consisting of ≈1,200 single transmembrane proteins in the human genome. The new interactions were confirmed using biophysical and cell-based methods for functional characterization of select receptor-ligand pairs. Results Using this technology Interleukin-20 receptor subunit alpha (IL20RA) was identified as the first counter-receptor for B7-H3. Furthermore, the natural killer cell receptor KIR2DL5A is identified as a new binding partner for PVR, an interaction that is fully validated using orthogonal methods and cellular assays. Here we show that KIR2DL5A engagement by PVR expressed on tumor cells results in reduced natural killer cell cytotoxicity. PVR deletion or treatment with an anti-KIR2DL5A antibody restored NK-mediated cytolysis of tumor cells. Additionally, competition assays show that PVR interacts with both TIGIT and KIR2DL5A on the cell surface, suggesting a previously unrecognized mechanism of action. Conclusion Here we developed a new platform for elucidation of secreted or membrane protein interactomes. The power of this technology is demonstrated by identification of new interactors for emerging therapeutic targets such as PVR or B7-H3. These results provide insights into Immune receptor biology and highlight potential new cellular targets, ultimately serving as a unique tool to inform therapeutic development. Legal entity responsible for the study The authors. Funding Genentech Inc. Disclosure All authors have declared no conflicts of interest.
Yvonne Franke - One of the best experts on this subject based on the ideXlab platform.
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A Platform for Extracellular Interactome Discovery Identifies Novel Functional Binding Partners for the Immune Receptors B7-H3/CD276 and PVR/CD155.
Molecular & cellular proteomics : MCP, 2019Co-Authors: Bushra Husain, Sree R. Ramani, Eugene Chiang, Isabelle Lehoux, Sairupa Paduchuri, Tia A Arena, Ashka Patel, Blair Wilson, Pamela Chan, Yvonne FrankeAbstract:Receptors expressed on the plasma membrane and their interacting partners critically regulate cellular communication during homeostasis and disease, and as such represent main therapeutic targets. Despite its importance for drug development, receptor-ligand proteomics has remained a daunting field, in part because of the challenges associated to the study of membrane-expressed proteins. Here, to enable sensitive detection of receptor-ligand interactions in high throughput, we implement a new platform, the Conditioned Media AlphaScreen, for interrogation of a library consisting of most single transmembrane human proteins. Using this method to study key Immune Receptors, we identify and further validate the interleukin receptor IL20RA as the first binding partner for the checkpoint inhibitor B7-H3. Further, KIR2DL5, a natural killer cell protein that had remained orphan, is uncovered as a functional binding partner for the poliovirus receptor (PVR). This interaction is characterized using orthogonal assays, which demonstrate that PVR specifically engages KIR2DL5 on natural killer cells leading to inhibition of cytotoxicity. Altogether, these results reveal unappreciated links between protein families that may importantly influence receptor-driven functions during disease. Applicable to any target of interest, this technology represents a versatile and powerful approach for elucidation of receptor-ligand interactomes, which is essential to understand basic aspects of the biology of the plasma membrane proteins and ultimately inform the development of novel therapeutic strategies.
Yusuke Saijo - One of the best experts on this subject based on the ideXlab platform.
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er mediated control for abundance quality and signaling of transmembrane Immune Receptors in plants
Frontiers in Plant Science, 2014Co-Authors: Nico Tintor, Yusuke SaijoAbstract:Plants recognize a wide range of microbes with cell-surface and intracellular Immune Receptors. Transmembrane pattern recognition Receptors (PRRs) initiate Immune responses upon recognition of cognate ligands characteristic of microbes or aberrant cellular states, designated microbe-associated molecular patterns or danger-associated molecular patterns (DAMPs), respectively.Pattern-triggered immunity provides a first line of defense that restricts the invasion and propagation of both adapted and non-adapted pathogens. Receptor kinases (RKs) and receptor-like proteins (RLPs) with an extracellular leucine-rich repeat or lysine-motif (LysM) domain are extensively used as PRRs. The correct folding of the extracellular domain of these Receptors is under quality control (QC) in the endoplasmic reticulum (ER), which thus provides a critical step in plant immunity. Genetic and structural insight suggests that ERQC regulates not only the abundance and quality of transmembrane Receptors but also affects signal sorting between multi-branched pathways downstream of the receptor. However, ERQC dysfunction can also positively stimulate plant immunity, possibly through cell death and DAMP signaling pathways.
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coiled coil domain dependent homodimerization of intracellular barley Immune Receptors defines a minimal functional module for triggering cell death
Cell Host & Microbe, 2011Co-Authors: Takaki Maekawa, Laurentiu N. Spiridon, Yusuke Saijo, Qianhua Shen, Wei Cheng, Armin Toller, Ewa Lukasik, Peiyuan Liu, Marius A Micluta, Imre E SomssichAbstract:Plants and animals have evolved structurally related innate Immune sensors, designated NLRs, to detect intracellular nonself molecules. NLRs are modular, consisting of N-terminal coiled-coil (CC) or TOLL/interleukin-1 receptor (TIR) domains, a central nucleotide-binding (NB) domain, and C-terminal leucine-rich repeats (LRRs). The polymorphic barley mildew A (MLA) locus encodes CC-containing allelic Immune Receptors recognizing effectors of the pathogenic powdery mildew fungus. We report the crystal structure of an MLA receptor's invariant CC domain, which reveals a rod-shaped homodimer. MLA Receptors also self-associate in vivo, but self-association appears to be independent of effector-triggered receptor activation. MLA CC mutants that fail to self-interact impair in planta cell death activity triggered by the CC domain alone and by an autoactive full-length MLA receptor that mimics its ATP-bound state. Thus, CC domain-dependent dimerization of the Immune sensor defines a minimal functional unit and implies a role for the dimeric CC module in downstream Immune signaling.
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ER quality control of Immune Receptors and regulators in plants.
Cellular microbiology, 2010Co-Authors: Yusuke SaijoAbstract:Like in animals, cell surface and intracellular Receptors mediate Immune recognition of potential microbial intruders in plants. Membrane-localized pattern recognition Receptors (PRRs) initiate Immune responses upon perception of cognate microbe-associated molecular patterns (MAMPs). MAMP-triggered immunity provides a first line of defence that restricts the invasion and propagation of both adapted and non-adapted pathogens. The Leu-rich repeat (LRR) receptor protein kinases (RKs) define a major class of trans-membrane Receptors in plants, of which some members are engaged in MAMP recognition and/or defence signalling. The endoplasmic reticulum (ER) quality control (QC) systems monitor N-glycosylation and folding states of the extracellular, ligand-binding LRR domains of LRR-RKs. Recent progress reveals a critical role of evolutionarily conserved ERQC components for different layers of plant immunity. N-glycosylation appears to play a role in ERQC fidelity rather than in ligand binding of LRR-RKs. Moreover, even closely related PRRs show receptor-specific requirements for N-glycosylation. These findings are reminiscent of the earlier defined function of the cytosolic chaperon complex for LRR domain-containing intracellular Immune Receptors. QC of the LRR domains might provide a basis not only for the maintenance but also for diversification of recognition specificities for Immune Receptors in plants.
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nuclear activity of mla Immune Receptors links isolate specific and basal disease resistance responses
Science, 2007Co-Authors: Qianhua Shen, Yusuke Saijo, Stefan Mauch, Christoph Biskup, Stephane Bieri, Beat Keller, Hikaru Seki, Bekir Ulker, Imre E Somssich, Paul SchulzelefertAbstract:Plant Immune responses are triggered by pattern recognition Receptors that detect conserved pathogen-associated molecular patterns (PAMPs) or by resistance (R) proteins recognizing isolate-specific pathogen effectors. We show that in barley, intracellular mildew A (MLA) R proteins function in the nucleus to confer resistance against the powdery mildew fungus. Recognition of the fungal avirulence A10 effector by MLA10 induces nuclear associations between receptor and WRKY transcription factors. The identified WRKY proteins act as repressors of PAMP-triggered basal defense. MLA appears to interfere with the WRKY repressor function, thereby de-repressing PAMP-triggered basal defense. Our findings reveal a mechanism by which these polymorphic Immune Receptors integrate distinct pathogen signals.
