Article

Structural linkage between ligand discrimination and receptor activation by type I interferons.

Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell (Impact Factor: 33.12). 08/2011; 146(4):621-32. DOI: 10.1016/j.cell.2011.06.048
Source: PubMed

ABSTRACT Type I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human type I IFN variants signal through the same cell-surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique among the cytokine receptor superfamily but conserved between different type I IFNs. Receptor-ligand cross-reactivity is enabled by conserved receptor-ligand "anchor points" interspersed among ligand-specific interactions that "tune" the relative IFN-binding affinities, in an apparent extracellular "ligand proofreading" mechanism that modulates biological activity. Functional differences between IFNs are linked to their respective receptor recognition chemistries, in concert with a ligand-induced conformational change in IFNAR1, that collectively control signal initiation and complex stability, ultimately regulating differential STAT phosphorylation profiles, receptor internalization rates, and downstream gene expression patterns.

0 Followers
 · 
164 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: While type I interferons (IFNs) are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral and bacterial infections. The underlying mechanisms by which type I IFNs promote susceptibility or severity include direct tissue damage by apoptosis induction or suppression of proliferation in tissue cells, immunopathology due to excessive inflammation, and cell death induced by TRAIL- and Fas-expressing immune cells, as well as immunosuppression through IL-10, IL-27, PD-L1, IL-1Ra, and other regulatory molecules that antagonize the induction or action of IL-1, IL-12, IL-17, IFN-γ, KC, and other effectors of the immune response. Bacterial superinfections following influenza infection are a prominent example of a situation where type I IFNs can misdirect the immune response. This review discusses current understanding of the parameters of signal strength, duration, timing, location, and cellular recipients that determine whether type I IFNs have beneficial or detrimental effects in infection.
    Journal of Interferon & Cytokine Research 02/2015; 35(4). DOI:10.1089/jir.2014.0227 · 3.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although type I interferon (IFN-I) is thought to be beneficial against microbial infections, persistent viral infections are characterized by high interferon signatures suggesting that IFN-I signaling may promote disease pathogenesis. During persistent lymphocytic choriomeningitis virus (LCMV) infection, IFNα and IFNβ are highly induced early after infection, and blocking IFN-I receptor (IFNAR) signaling promotes virus clearance. We assessed the specific roles of IFNβ versus IFNα in controlling LCMV infection. While blockade of IFNβ alone does not alter early viral dissemination, it is important in determining lymphoid structure, lymphocyte migration, and anti-viral T cell responses that lead to accelerated virus clearance, approximating what occurs during attenuation of IFNAR signaling. Comparatively, blockade of IFNα was not associated with improved viral control, but with early dissemination of virus. Thus, despite their use of the same receptor, IFNβ and IFNα have unique and distinguishable biologic functions, with IFNβ being mainly responsible for promoting viral persistence. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 05/2015; 17(5):653-61. DOI:10.1016/j.chom.2015.04.005 · 12.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Most cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to “tune” signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand-independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems.
    Cell 03/2015; 160:1-13. DOI:10.1016/j.cell.2015.02.011 · 33.12 Impact Factor