The Short Form of the Interferon α/β Receptor Chain 2 Acts as a Dominant Negative for Type I Interferon Action

Ligand-induced endocytosis and lysosomal degradation of cognate receptors regulate the extent of cell signaling. Along with linear endocytic motifs that recruit the adaptin protein complex 2 (AP2)–clathrin molecules, monoubiquitination of receptors has emerged as a major endocytic signal. By investigating ubiquitin-dependent lysosomal degradation of the interferon (IFN)-α/β receptor 1 (IFNAR1) subunit of the type I IFN receptor, we reveal that IFNAR1 is polyubiquitinated via both Lys48- and Lys63-linked chains. The SCFβTrcp (Skp1–Cullin1–F-box complex) E3 ubiquitin ligase that mediates IFNAR1 ubiquitination and degradation in cells can conjugate both types of chains in vitro. Although either polyubiquitin linkage suffices for postinternalization sorting, both types of chains are necessary but not sufficient for robust IFNAR1 turnover and internalization. These processes also depend on the proximity of ubiquitin-acceptor lysines to a linear endocytic motif and on its integrity. Furthermore, ubiquitination of IFNAR1 promotes its interaction with the AP2 adaptin complex that is required for the robust internalization of IFNAR1, implicating cooperation between site-specific ubiquitination and the linear endocytic motif in regulating this process.

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Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Blood ◽

10.1182/blood-2010-12-325373 ◽

2011 ◽

Vol 118 (15) ◽

pp. 4179-4187 ◽

Cited By ~ 29

Author(s):

Sabyasachi Bhattacharya ◽

Hui Zheng ◽

Christos Tzimas ◽

Martin Carroll ◽

Darren P. Baker ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Protein Kinase ◽

Imatinib Mesylate ◽

Myeloid Leukemia ◽

Primary Treatment ◽

Interferon Α ◽

Type I ◽

Constitutive Activity ◽

Β Receptor ◽

The Relationship

Abstract Constitutive activity of Bcr-abl fusion protein kinase causes chronic myeloid leukemia (CML). Inhibitors of Bcr-abl such as imatinib mesylate have replaced the cytokine IFNα as the primary treatment for the management of patients with this malignancy. We found that pretreatment of CML cells with imatinib mesylate augments the antigrowth effects of IFNα. Furthermore, introduction of Bcr-abl into non-CML cells inhibits the cellular responses to IFNα. This inhibition is mediated via a mechanism that involves activation of protein kinase D2. The latter promotes an accelerated phosphorylation-dependent degradation of the interferon-α/β receptor 1 chain of the type I interferon receptor, leading to attenuation of IFNα signaling. We discuss the relationship between Bcr-abl activity and IFNα signaling as a molecular basis of the combination of inhibitors of Bcr-abl and IFNα for CML treatment.

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The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis

mBio ◽

10.1128/mbio.00437-16 ◽

2016 ◽

Vol 7 (2) ◽

Cited By ~ 19

Author(s):

Douglas R. Wilcox ◽

Stephen S. Folmsbee ◽

William J. Muller ◽

Richard Longnecker

Keyword(s):

Choroid Plexus ◽

Type I Interferon ◽

Adult Brain ◽

Interferon Response ◽

Type I ◽

Β Receptor ◽

Simplex Virus ◽

The Brain ◽

Hsv 1

ABSTRACTNewborns are significantly more susceptible to severe viral encephalitis than adults, with differences in the host response to infection implicated as a major factor. However, the specific host signaling pathways responsible for differences in susceptibility and neurologic morbidity have remained unknown. In a murine model of HSV encephalitis, we demonstrated that the choroid plexus (CP) is susceptible to herpes simplex virus 1 (HSV-1) early in infection of the newborn but not the adult brain. We confirmed susceptibility of the CP to HSV infection in a human case of newborn HSV encephalitis. We investigated components of the type I interferon (IFN) response in the murine brain that might account for differences in cell susceptibility and found that newborns have a dampened interferon response and significantly lower basal levels of the alpha/beta interferon (IFN-α/β) receptor (IFNAR) than do adults. To test the contribution of IFNAR to restricting infection from the CP, we infected IFNAR knockout (KO) adult mice, which showed restored CP susceptibility to HSV-1 infection in the adult. Furthermore, reduced IFNAR levels did not account for differences we found in the basal levels of several other innate signaling proteins in the wild-type newborn and the adult, including protein kinase R (PKR), that suggested specific regulation of innate immunity in the developing brain. Viral targeting of the CP, a region of the brain that plays a critical role in neurodevelopment, provides a link between newborn susceptibility to HSV and long-term neurologic morbidity among survivors of newborn HSV encephalitis.IMPORTANCECompared to adults, newborns are significantly more susceptible to severe disease following HSV infection. Over half of newborn HSV infections result in disseminated disease or encephalitis, with long-term neurologic morbidity in 2/3 of encephalitis survivors. We investigated differences in host cell susceptibility between newborns and adults that contribute to severe central nervous system disease in the newborn. We found that, unlike the adult brain, the newborn choroid plexus (CP) was susceptible early in HSV-1 infection. We demonstrated that IFN-α/β receptor levels are lower in the newborn brain than in the adult brain and that deletion of this receptor restores susceptibility of the CP in the adult brain. The CP serves as a barrier between the blood and the cerebrospinal fluid and plays a role in proper neurodevelopment. Susceptibility of the newborn choroid plexus to HSV-1 has important implications in viral spread to the brain and, also, in the neurologic morbidity following HSV encephalitis.

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Type I interferon is selectively required by dendritic cells for immune rejection of tumors

Journal of Experimental Medicine ◽

10.1084/jem.20101158 ◽

2011 ◽

Vol 208 (10) ◽

pp. 1989-2003 ◽

Cited By ~ 524

Author(s):

Mark S. Diamond ◽

Michelle Kinder ◽

Hirokazu Matsushita ◽

Mona Mashayekhi ◽

Gavin P. Dunn ◽

...

Keyword(s):

Dendritic Cells ◽

Type I Interferon ◽

Tumor Rejection ◽

Type I ◽

Type I Ifn ◽

Cancer Immunoediting ◽

Cross Presentation ◽

Tumor Immunogenicity ◽

Β Receptor ◽

Macrophage Populations

Cancer immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/β) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN’s actions. However, the specific cells affected by IFN-α/β and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elimination. We further show that mice lacking IFNAR1 (IFN-α/β receptor 1) in dendritic cells (DCs; Itgax-Cre+Ifnar1f/f mice) cannot reject highly immunogenic tumor cells and that CD8α+ DCs from these mice display defects in antigen cross-presentation to CD8+ T cells. In contrast, mice depleted of NK cells or mice that lack IFNAR1 in granulocytes and macrophage populations reject these tumors normally. Thus, DCs and specifically CD8α+ DCs are functionally relevant targets of endogenous type I IFN during lymphocyte-mediated tumor rejection.

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Vaccinia Virus B18R Gene Encodes a Type I Interferon-binding Protein That Blocks Interferon α Transmembrane Signaling

Journal of Biological Chemistry ◽

10.1074/jbc.270.27.15974 ◽

1995 ◽

Vol 270 (27) ◽

pp. 15974-15978 ◽

Cited By ~ 245

Author(s):

Oscar R. Colamonici ◽

Paul Domanski ◽

Sharon M. Sweitzer ◽

Andrew Larner ◽

R. Mark L. Buller

Keyword(s):

Vaccinia Virus ◽

Type I Interferon ◽

Binding Protein ◽

Interferon Α ◽

Type I ◽

Transmembrane Signaling

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miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells

Blood ◽

10.1182/blood-2010-04-280156 ◽

2010 ◽

Vol 116 (26) ◽

pp. 5885-5894 ◽

Cited By ~ 171

Author(s):

Haibo Zhou ◽

Xinfang Huang ◽

Huijuan Cui ◽

Xiaobing Luo ◽

Yuanjia Tang ◽

...

Keyword(s):

Gene Expression Regulation ◽

Type I Interferon ◽

Early Stage ◽

Plasmacytoid Dendritic Cell ◽

Interferon Α ◽

Type I ◽

Interferon Production ◽

Novel Mirna ◽

Star Form ◽

Single Precursor

Abstract The recent discovery of microRNAs (miRNAs) has revealed a new layer of gene expression regulation, affecting the immune system. Here, we identify their roles in regulating human plasmacytoid dendritic cell (PDC) activation. miRNA profiling showed the significantly differential expression of 19 miRNAs in PDCs after Toll-like receptor 7 (TLR7) stimulation, among which miR-155* and miR-155 were the most highly induced. Although they were processed from a single precursor and were both induced by TLR7 through the c-Jun N-terminal kinase pathway, miR-155* and miR-155 had opposite effects on the regulation of type I interferon production by PDC. Further study indicated that miR-155* augmented interferon-α/β expression by suppressing IRAKM, whereas miR-155 inhibited their expression by targeting TAB2. Kinetic analysis of miR-155* and miR-155 induction revealed that miR-155* was mainly induced in the early stage of stimulation, and that miR-155 was mainly induced in the later stage, suggesting their cooperative involvement in PDC activation. Finally, we demonstrated that miR-155* and miR-155 were inversely regulated by autocrine/paracrine type I interferon and TLR7-activated KHSRP at the posttranscriptional level, which led to their different dynamic induction by TLR7. Thus, our study identified and validated novel miRNA-protein networks involved in regulating PDC activation.

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Plasmacytoid Dendritic Cells Mediate Myocardial Ischemia/Reperfusion Injury by Secreting Type I Interferons

Journal of the American Heart Association ◽

10.1161/jaha.121.020754 ◽

2021 ◽

Author(s):

Lina Lai ◽

Aimee Zhang ◽

Boris Yang ◽

Eric J. Charles ◽

Irving L. Kron ◽

...

Keyword(s):

Myocardial Ischemia ◽

Infarct Size ◽

Reperfusion Injury ◽

Cyclic Gmp ◽

Type I Interferon ◽

Ischemia Reperfusion ◽

Interferon Α ◽

Type I ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion

Background We previously demonstrated that ischemically injured cardiomyocytes release cell‐free DNA and HMGB1 (high mobility group box 1 protein) into circulation during reperfusion, activating proinflammatory responses and ultimately exacerbating reperfusion injury. We hypothesize that cell‐free DNA and HMGB1 mediate myocardial ischemia‐reperfusion injury by stimulating plasmacytoid dendritic cells (pDCs) to secrete type I interferon (IFN‐I). Methods and Results C57BL/6 and interferon alpha receptor‐1 knockout mice underwent 40 minutes of left coronary artery occlusion followed by 60 minutes of reperfusion (40′/60′ IR) before infarct size was evaluated by 2,3,5‐Triphenyltetrazolium chloride–Blue staining. Cardiac perfusate was acquired in ischemic hearts without reperfusion by antegrade perfusion of the isolated heart. Flow cytometry in pDC‐depleted mice treated with multiple doses of plasmacytoid dendritic cell antigen‐1 antibody via intraperitoneal injection demonstrated plasmacytoid dendritic cell antigen‐1 antibody treatment had no effect on conventional splenic dendritic cells but significantly reduced splenic pDCs by 60%. pDC‐depleted mice had significantly smaller infarct size and decreased plasma interferon‐α and interferon‐β compared with control. Blockade of the type I interferon signaling pathway with cyclic GMP‐AMP synthase inhibitor, stimulator of interferon genes antibody, or interferon regulatory factor 3 antibody upon reperfusion similarly significantly attenuated infarct size by 45%. Plasma levels of interferon‐α and interferon‐β were significantly reduced in cyclic GMP‐AMP synthase inhibitor‐treated mice. Infarct size was significantly reduced by >30% in type I interferon receptor monoclonal antibody–treated mice and interferon alpha receptor‐1 knockout mice. In splenocyte culture, 40′/0′ cardiac perfusate treatment stimulated interferon‐α and interferon‐β production; however, this effect disappeared in the presence of cyclic GMP‐AMP synthase inhibitor. Conclusions Type I interferon production is stimulated following myocardial ischemia by cardiogenic cell‐free DNA/HMGB1 in a pDC‐dependent manner, and subsequently activates type I interferon receptors to exacerbate reperfusion injury. These results identify new potential therapeutic targets to attenuate myocardial ischemia‐reperfusion injury.

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The role of the Type I interferon response in the resistance of mice to filovirus infection

Journal of General Virology ◽

10.1099/0022-1317-82-6-1365 ◽

2001 ◽

Vol 82 (6) ◽

pp. 1365-1373 ◽

Cited By ~ 153

Author(s):

Mike Bray

Keyword(s):

Type I Interferon ◽

Antiviral Drug ◽

Interferon Response ◽

Type I ◽

Antibody Treatment ◽

Adult Mice ◽

Lethal Infection ◽

Series Of Experiments ◽

Β Receptor ◽

Immunocompetent Mice

Adult immunocompetent mice inoculated with Ebola (EBO) or Marburg (MBG) virus do not become ill. A suckling-mouse-passaged variant of EBO Zaire ’76 (‘mouse-adapted EBO-Z’) causes rapidly lethal infection in adult mice after intraperitoneal (i.p.) inoculation, but does not cause apparent disease when inoculated subcutaneously (s.c.). A series of experiments showed that both forms of resistance to infection are mediated by the Type I interferon response. Mice lacking the cell-surface IFN-α/β receptor died within a week after inoculation of EBO-Z ’76, EBO Sudan, MBG Musoke or MBG Ravn, or after s.c. challenge with mouse-adapted EBO-Z. EBO Reston and EBO Ivory Coast did not cause illness, but immunized the mice against subsequent challenge with mouse-adapted EBO-Z. Normal adult mice treated with antibodies against murine IFN-α/β could also be lethally infected with i.p.-inoculated EBO-Z ’76 or EBO Sudan and with s.c.-inoculated mouse-adapted EBO-Z. Severe combined immunodeficient (SCID) mice became ill 3–4 weeks after inoculation with EBO-Z ’76, EBO Sudan or MBG Ravn, but not the other viruses. Treatment with anti-IFN-α/β antibodies markedly accelerated the course of EBO-Z ’76 infection. Antibody treatment blocked the effect of a potent antiviral drug, 3-deazaneplanocin A, indicating that successful filovirus therapy may require the active participation of the Type I IFN response. Mice lacking an IFN-α/β response resemble primates in their susceptibility to rapidly progressive, overwhelming filovirus infection. The outcome of filovirus transfer between animal species appears to be determined by interactions between the virus and the innate immune response.

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