Structure of the IFN-lambda3/IFN-lambdaR1/IL-10Rbeta receptor complex with an engineered IL-10Rbeta
Ontology highlight
ABSTRACT:
SUBMITTER: Minglei Zhao
PROVIDER: EMPIAR-12502 | biostudies-other |
REPOSITORIES: biostudies-other
Publications
Structural studies of the IFNλ4 receptor complex using cryoEM enabled by protein engineering.
Grubbe William S WS Zhang Bixia B Kauffman Aileen A Byléhn Fabian F Padoł Kasia K Jung Hae-Gwang HG Park Seung Bum SB Priest Jessica M JM Özkan Engin E de Pablo Juan J JJ Liang T Jake TJ Zhao Minglei M Mendoza Juan L JL
Nature communications 20250118 1
IFNλ4 has posed a conundrum in human immunology since its discovery in 2013, with its expression linked to complications with viral clearance. While genetic and cellular studies revealed the detrimental effects of IFNλ4 expression, extensive structural and functional characterization has been limited by the inability to express and purify the protein, complicating explanations of its paradoxical behavior. In this work, we report a method for robust production of IFNλ4. We then use yeast surface ...[more]
Similar Datasets
Project description:The recently discovered IFN-λ4 has been found to have antiviral activity against several viruses. However, it's unknown whether IFN-λ4 can inhibit HIV infection. Here, we show that IFN-λ4 could suppress HIV infection of macrophages. This IFN-λ4-mediated HIV inhibition was compromised by the antibodies against IFN-λ receptor complex, IFN-λR1/IL-10R2. IFN-λ4 enhanced the phosphorylation of STAT1, and induced antiviral interferon-stimulated genes. These findings indicated that IFN-λ4 can inhibit HIV via JAK/STAT signalling pathway.
| S-EPMC6286684 | biostudies-literature
Project description:Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface receptors, IL-27Rα and gp130, results in activation of receptor-associated Janus Kinases and nuclear translocation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT3 transcription factors. Despite the emerging therapeutic importance of this cytokine axis in cancer and autoimmunity, a molecular blueprint of the IL-27 receptor signaling complex, and its relation to other gp130/IL-12 family cytokines, is currently unclear. We used cryogenic-electron microscopy to determine the quaternary structure of IL-27, composed of p28 and Epstein-Barr Virus-Induced 3 (Ebi3) subunits, bound to receptors, IL-27Rα and gp130. The resulting 3.47 Å resolution structure revealed a three-site assembly mechanism nucleated by the central p28 subunit of the cytokine. The overall topology and molecular details of this binding are reminiscent of IL-6 but distinct from related heterodimeric cytokines IL-12 and IL-23. These results indicate distinct receptor assembly mechanisms used by heterodimeric cytokines with important consequences for targeted agonism and antagonism of IL-27 signaling.
| S-EPMC9142143 | biostudies-literature
Project description:Interleukin-1 (IL-1)-family cytokines are mediators of innate and adaptive immunity. They exert proinflammatory effects by binding a primary receptor that recruits a receptor accessory protein to form a signaling-competent heterotrimeric complex. Here we present the crystal structure of IL-1? bound to its primary receptor IL-1RI and its receptor accessory protein IL-1RAcP, providing insight into how IL-1-type cytokines initiate signaling and revealing an evolutionary relationship with the fibroblast growth factor receptor family.
| S-EPMC4006550 | biostudies-literature
Project description:Type III interferons (IFN-λs) signal through a heterodimeric receptor complex composed of the IFN-λR1 subunit, specific for IFN-λs, and interleukin-10Rβ (IL-10Rβ), which is shared by multiple cytokines in the IL-10 superfamily. Low affinity of IL-10Rβ for cytokines has impeded efforts aimed at crystallizing cytokine-receptor complexes. We used yeast surface display to engineer a higher-affinity IFN-λ variant, H11, which enabled crystallization of the ternary complex. The structure revealed that IL-10Rβ uses a network of tyrosine residues as hydrophobic anchor points to engage IL-10 family cytokines that present complementary hydrophobic binding patches, explaining its role as both a cross-reactive but cytokine-specific receptor. H11 elicited increased anti-proliferative and antiviral activities in vitro and in vivo. In contrast, engineered higher-affinity type I IFNs did not increase antiviral potency over wild-type type I IFNs. Our findings provide insight into cytokine recognition by the IL-10R family and highlight the plasticity of type III interferon signaling and its therapeutic potential.
| S-EPMC5510750 | biostudies-literature
Project description:IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2R alpha, IL-2R beta, and gamma(c). Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 A resolution. The quaternary structure is consistent with a stepwise assembly from IL-2/IL-2R alpha to IL-2/IL-2R alpha/IL-2R beta to IL-2/IL-2R alpha/IL-2R beta/gamma(c). The IL-2R alpha subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge-charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2R alpha with IL-2 at the cell surface. Surprisingly, IL-2R alpha makes no contacts with IL-2R beta or gamma(c), and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2R alpha to deliver IL-2 to the signaling complex and act as regulator of signal transduction. Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2R beta and gamma(c) subunits. Helix A of IL-2 wedges tightly between IL-2R beta and gamma(c) to form a three-way junction that coalesces into a composite binding site for the final gamma(c) recruitment. The IL-2/gamma(c) interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes.
| S-EPMC1413841 | biostudies-literature
Project description:Interleukin-10 (IL-10) is an immunomodulatory cytokine that plays important roles in terminating inflammatory responses and preventing tissue damage resulting from autoimmunity. Although these anti-inflammatory actions have led to considerable clinical interest, efforts to exploit IL-10 therapeutically have been hindered by the highly pleiotropic nature of IL-10 and its ability to elicit proinflammatory effects in vivo. In this structural snapshot, we review the recent cryo-EM structure of the IL-10 receptor signaling complex, highlighting its unique structural features, insights into the mechanism of receptor sharing by the IL-10 cytokine family, and the implications for manipulating IL-10 signaling therapeutically.
| S-EPMC9222382 | biostudies-literature
Project description:IL-15 is involved in regulating host defense and inflammation. Monocytes produce the biologically active cell surface IL-15 in response to IFN-γ. Although aging can alter the immune system, little is known about whether and how aging affects IFN-γ-mediated IL-15 production in human monocytes. We showed that monocytes of healthy older adults (age ≥ 65) had increased cell surface IL-15 expression in response to IFN-γ compared to those of healthy young adults (age ≤ 40). This finding stems in part from increased IFN-γ receptor (R)1/2 expression on monocytes in older adults, leading to enhanced STAT1 activation and interferon regulatory factor 1 synthesis with increased IL15 gene expression. Our study suggests that with aging the IFN-γ-mediated IL-15 production pathway in human monocytes is uncompromised, but rather augmented, and could be considered as a therapeutic target point to modulate host defense and inflammation in older adults.
| S-EPMC4018768 | biostudies-literature
Project description:Cytokines secreted at sites of inflammation impact the onset, progression, and resolution of inflammation. In this article, we investigated potential proresolving mechanisms of IFN-? in models of inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-? selectively induced the expression of IL-10R1 on intestinal epithelia. Further analysis revealed that IL-10R1 was expressed predominantly on the apical membrane of polarized epithelial cells. Receptor activation functionally induced canonical IL-10 target gene expression in epithelia, concomitant with enhanced barrier restitution. Furthermore, knockdown of IL-10R1 in intestinal epithelial cells results in impaired barrier function in vitro. Colonic tissue isolated from murine colitis revealed that levels of IL-10R1 and suppressor of cytokine signaling 3 were increased in the epithelium and coincided with increased tissue IFN-? and IL-10 cytokines. In parallel, studies showed that treatment of mice with rIFN-? was sufficient to drive expression of IL-10R1 in the colonic epithelium. Studies of dextran sodium sulfate colitis in intestinal epithelial-specific IL-10R1-null mice revealed a remarkable increase in disease susceptibility associated with increased intestinal permeability. Together, these results provide novel insight into the crucial and underappreciated role of epithelial IL-10 signaling in the maintenance and restitution of epithelial barrier and of the temporal regulation of these pathways by IFN-?.
| S-EPMC4042245 | biostudies-literature
Project description:IL-31 is a T cell-derived cytokine that signals via a heterodimeric receptor composed of IL-31R? and oncostatin M receptor ?. Although several studies have aimed to investigate IL-31-mediated effects, the biological functions of this cytokine are currently not well understood. IL-31 expression correlates with the expression of IL-4 and IL-13 and is associated with atopic dermatitis in humans, indicating that IL-31 is involved in Th2-mediated skin inflammation. Because dendritic cells are the main activators of Th cell responses, we posed the question of whether dendritic cells express the IL-31R complex and govern immune responses triggered by IL-31. In the current study, we report that primary human CD1c(+) as well as monocyte-derived dendritic cells significantly upregulate the IL-31R? receptor chain upon stimulation with IFN-?. EMSAs, chromatin immunoprecipitation assays, and small interfering RNA-based silencing assays revealed that STAT1 is the main transcription factor involved in IFN-?-dependent IL-31R? expression. Subsequent IL-31 stimulation resulted in a dose-dependent release of proinflammatory mediators, including TNF-?, IL-6, CXCL8, CCL2, CCL5, and CCL22. Because these cytokines are crucially involved in skin inflammation, we hypothesize that IL-31-specific activation of dendritic cells may be part of a positive feedback loop driving the progression of inflammatory skin diseases.
| S-EPMC4766741 | biostudies-literature
Project description:Engineered receptors play increasingly important roles in transformative cell-based therapies. However, the structural mechanisms that drive differences in performance across receptor designs are often poorly understood. Recent advances in protein structural prediction tools have enabled the modeling of virtually any user-defined protein, but how these tools might build understanding of engineered receptors has yet to be fully explored. In this study, we employed structural modeling tools to perform post hoc analyses to investigate whether predicted structural features might explain observed functional variation. We selected a recently reported library of receptors derived from natural cytokine receptors as a case study, generated structural models, and from these predictions quantified a set of structural features that plausibly impact receptor performance. Encouragingly, for a subset of receptors, structural features explained considerable variation in performance, and trends were largely conserved across structurally diverse receptor sets. This work indicates potential for structure prediction-guided synthetic receptor engineering.
| S-EPMC11581020 | biostudies-literature