scholarly journals STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome

2019 ◽  
Author(s):  
Natacha Zanin ◽  
Cédric M. Blouin ◽  
Christine Viaris de Lesegno ◽  
Daniela Chmiest ◽  
Ludger Johannes ◽  
...  
Keyword(s):  
Early Endosome ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Interferon Α ◽  
Type I ◽  
Endosomal Sorting ◽  
Early Endosomes ◽  
Stat Signaling ◽  
Molecular Machinery ◽  
Β Receptor

ABSTRACTActivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway by type I interferons (IFN) requires clathrin-dependent endocytosis of the IFN-α/β receptor (IFNAR). The molecular machinery that brings about the selective activation of IFN-α/β-induced JAK/STAT signaling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and the TYK2 Janus kinase at the plasma membrane prevents the activation of TYK2 by type I IFNs. IFN-α stimulated endocytosis leads to the interaction of IFNAR1 with Hrs on early endosomes, which then relieves TYK2 inhibition by STAM and thereby allows for TYK2 and IFNAR signaling. In contrast, IFN-β stimulation results in sorting of IFNAR to a distinct endosomal subdomain where the receptor is activated independently from Hrs. Our results identify the molecular machinery that controls the spatiotemporal activation of TYK2 and establish the central role of endosomal sorting in the differential regulation of JAK/STAT signaling by IFN-α and IFN-β.SummaryThe spatiotemporal activation of JAK/STAT signaling by IFN-α is controlled by STAM association with Hrs at the early endosome.

Immune response to dermatomyositis-specific autoantigen, transcriptional intermediary factor 1γ can result in experimental myositis

2021 ◽  
pp. annrheumdis-2020-218661
Author(s):  
Naoko Okiyama ◽  
Yuki Ichimura ◽  
Miwako Shobo ◽  
Ryota Tanaka ◽  
Noriko Kubota ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Kinase Inhibitor ◽  
Inflammatory Myopathy ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Interferon Α ◽  
Muscle Fibres ◽  
Type I ◽  
Wild Type

ObjectivesTo investigate whether autoimmunity to transcriptional intermediary factor 1 (TIF1)γ, a ubiquitous nuclear autoantigen for myositis-specific autoantibodies detected in patients with dermatomyositis (DM) is pathogenetic for inflammatory myopathy.MethodsWild-type, β2-microglobulin-null, perforin-null, Igμ‐null and interferon α/β receptor (IFNAR)-null mice were immunised with recombinant human TIF1γ whole protein. A thymidine incorporation assay was performed using lymph node T cells from TIF1γ-immunised mice. Plasma was analysed using immunoprecipitation followed by western blot analysis and enzyme-linked immunosorbent assays. Femoral muscles were histologically and immunohistochemically evaluated. CD8+ or CD4+ T cells isolated from lymph node T cells or IgG purified from plasma were adoptively transferred to naïve mice. TIF1γ-immunised mice were treated with anti-CD8 depleting antibody and a Janus kinase inhibitor, tofacitinib.ResultsImmunisation with TIF1γ-induced experimental myositis presenting with necrosis/atrophy of muscle fibres accompanied by CD8+ T cell infiltration successfully in wild-type mice, in which TIF1γ-specific T cells and antihuman and murine TIF1γ IgG antibodies were detected. The incidence and severity of myositis were significantly lower in β₂-microglobulin-null, perforin-null, CD8-depleted or IFNAR-null mice, while Igμ‐null mice developed myositis normally. Adoptive transfer of CD8+ T cells induced myositis in recipients, while transfer of CD4+ T cells or IgG did not. Treatment with tofacitinib inhibited TIF1γ-induced myositis.ConclusionsHere we show that TIF1γ is immunogenic enough to cause experimental myositis, in which CD8+ T cells and type I interferons, but not CD4+ T cells, B cells or antibodies, are required. This murine model would be a tool for understanding the pathologies of DM.

scholarly journals Interferon-Independent Upregulation of Interferon-Stimulated Genes during Human Cytomegalovirus Infection is Dependent on IRF3 Expression

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 246 ◽  
Author(s):  
Caroline Ashley ◽  
Allison Abendroth ◽  
Brian McSharry ◽  
Barry Slobedman
Keyword(s):  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Human Fibroblasts ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Interferon Stimulated Genes ◽  
Stat Signaling ◽  
Isg15 Expression

The antiviral activity of type I interferons (IFNs) is primarily mediated by interferon-stimulated genes (ISGs). Induction of ISG transcription is achieved when type I IFNs bind to their cognate receptor and activate the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathways. Recently it has become clear that a number of viruses are capable of directly upregulating a subset of ISGs in the absence of type I IFN production. Using cells engineered to block either the response to, or production of type I IFN, the regulation of IFN-independent ISGs was examined in the context of human cytomegalovirus (HCMV) infection. Several ISGs, including IFIT1, IFIT2, IFIT3, Mx1, Mx2, CXCL10 and ISG15 were found to be upregulated transcriptionally following HCMV infection independently of type I IFN-initiated JAK-STAT signaling, but dependent on intact IRF3 signaling. ISG15 protein regulation mirrored that of its transcript with IFNβ neutralization failing to completely inhibit ISG15 expression post HCMV infection. In addition, no detectable ISG15 protein expression was observed following HCMV infection in IRF3 knockdown CRISPR/Cas-9 clones indicating that IFN-independent control of ISG expression during HCMV infection of human fibroblasts is absolutely dependent on IRF3 expression.

scholarly journals Site-specific ubiquitination exposes a linear motif to promote interferon-α receptor endocytosis

2007 ◽  
Vol 179 (5) ◽  
pp. 935-950 ◽  
Author(s):  
K.G. Suresh Kumar ◽  
Hervé Barriere ◽  
Christopher J. Carbone ◽  
Jianghuai Liu ◽  
Gayathri Swaminathan ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Interferon Α ◽  
Type I ◽  
Lysosomal Degradation ◽  
Linear Motif ◽  
Site Specific ◽  
Receptor Endocytosis ◽  
Β Receptor

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.

scholarly journals Targeting JAK/STAT pathway in Takayasu’s arteritis

2020 ◽  
Vol 79 (7) ◽  
pp. 951-959 ◽  
Author(s):  
Paul Régnier ◽  
Alexandre Le Joncour ◽  
Anna Maciejewski-Duval ◽  
Anne-Claire Desbois ◽  
Cloé Comarmond ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Takayasu’S Arteritis ◽  
Signalling Pathway ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Takayasu's Arteritis

ObjectiveTakayasu’s arteritis (TAK) is a large vessel vasculitis with important infiltration of proinflammatory T cells in the aorta and its main branches, but its aetiology is still unknown. Our work aims to explore the involvement of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signalling pathway in proinflammatory T cells differentiation and disease activity of TAK.MethodsWe analysed transcriptome and interferons gene signatures of fluorescence-activated cell sorting (FACS-sorted) CD4+ and CD8+ T cells from healthy donors (HD) and in 25 TAK (median age of 37.6 years including 21 active TAK with National Institutes of Health (NIH) score >1). Then we tested, in vitro and in vivo, the effects of JAK inhibitors (JAKinibs) in TAK.ResultsTranscriptome analysis showed 248 and 432 significantly dysregulated genes for CD4+ and CD8+ samples between HD and TAK, respectively. Among dysregulated genes, we highlighted a great enrichment for pathways linked to type I and type II interferons, JAK/STAT and cytokines/chemokines-related signalling in TAK. We confirmed by Real Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) the upregulation of type I interferons gene signature in TAK as compared with HD. JAKinibs induced both in vitro and in vivo a significant reduction of CD25 expression by CD4+ and CD8+ T cells, a significant decrease of type 1 helper T cells (Th1) and Th17 cells and an increase of Tregs cells in TAK. JAKinibs also decreased C reactive protein level, NIH score and corticosteroid dose in TAK patients.ConclusionsJAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.

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

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4179-4187 ◽  
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.

scholarly journals TYK2 activity promotes ligand-induced IFNAR1 proteolysis

2006 ◽  
Vol 397 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Zrinka Marijanovic ◽  
Josiane Ragimbeau ◽  
K. G. Suresh Kumar ◽  
Serge Y. Fuchs ◽  
Sandra Pellegrini
Keyword(s):  
Tyrosine Kinases ◽  
Janus Kinase ◽  
Serine Phosphorylation ◽  
Interferon Α ◽  
Type I ◽  
Major Mechanism ◽  
Catalytic Activation ◽  
Janus Kinase 1 ◽  
Lysosomal Proteolysis ◽  
Catalytic Role

The type I IFNR (interferon receptor) is a heterodimer composed of two transmembrane chains, IFNAR1 (interferon-α receptor 1 subunit) and IFNAR2, which are associated with the tyrosine kinases Tyk2 and Jak1 (Janus kinase 1) respectively. Ligand-induced down-regulation of the type I IFNR is a major mechanism of negative regulation of cellular signalling and involves the internalization and lysosomal degradation of IFNAR1. IFNα promotes the phosphorylation of IFNAR1 on Ser535, followed by recruitment of the E3 ubiquitin ligase, β-TrCP2 (β-transducin repeats-containing protein 2), ubiquitination of IFNAR1 and proteolysis. The non-catalytic role of Tyk2 in sustaining the steady-state IFNAR1 level at the plasma membrane is well documented; however, little is known about the function of Tyk2 in the steps that precede and succeed serine phosphorylation and ubiquitination of IFNAR1 in response to ligand binding. In the present study, we show that catalytic activation of Tyk2 is not essential for IFNAR1 internalization, but is required for ligand-induced IFNAR1 serine phosphorylation, ubiquitination and efficient lysosomal proteolysis.

scholarly journals Viral infection enhances vomocytosis of intracellular fungi via Type I interferons

2019 ◽  
Author(s):  
Paula I Seoane ◽  
Leanne M. Taylor-Smith ◽  
David Stirling ◽  
Lucy C. K. Bell ◽  
Mahdad Noursadeghi ◽  
...  
Keyword(s):  
Viral Infection ◽  
Cryptococcus Neoformans ◽  
Real Life ◽  
Innate Immune ◽  
Type I Interferons ◽  
Multiple Infections ◽  
Interferon Α ◽  
Type I ◽  
Viral Pathogens ◽  
Context Cues

AbstractCryptococcus neoformans is an opportunistic human pathogen, which causes serious disease in immunocompromised hosts. Infection with this pathogen is particularly relevant in HIV+ patients, where it leads to around 200,000 deaths per annum. A key feature of cryptococcal pathogenesis is the ability of the fungus to survive and replicate within the phagosome of macrophages, as well as its ability to escape via a novel non-lytic mechanism known as vomocytosis. We have been exploring whether viral infection affects the interaction between C. neoformans and macrophages. Here we show that viral infection enhances cryptococcal vomocytosis without altering phagocytosis or intracellular proliferation of the fungus. This effect occurs with distinct, unrelated human viral pathogens and is recapitulated when macrophages are stimulated with the anti-viral cytokine interferon alpha (IFNα). Importantly, the effect is abrogated when type-I interferon signalling is blocked, thus underscoring the importance of type-I interferons in this phenomenon. Our results highlight the importance of incorporating specific context cues while studying host-pathogen interactions. By doing so, we found that acute viral infection may trigger the release of latent cryptococci from intracellular compartments, with significant consequences for disease progression.Non-Technical Author SummaryInfectious diseases are typically studied in the laboratory in isolation, but in real life people often encounter multiple infections simultaneously. Here we investigate how the innate immune response to the fatal fungus Cryptococcus neoformans is influenced by viral coinfection. Whilst virally-infected macrophages retain a normal capacity to engulf and kill Cryptococci, they demonstrate a dramatically enhanced propensity to expel them via the process known as non-lytic expulsion or vomocytosis. Activation of vomocytosis is independent of the type of virus encountered, since both HIV and measles (two entirely unrelated viral pathogens) trigger the same effect. Instead it is driven by interferon-α, a generic ‘antiviral’ response, which signals back to the infected macrophage, triggering expulsion of the fungus. We propose that this hitherto unobserved phenomenon represents a ‘reprioritisation’ pathway for innate immune cells, by which they can alter the frequency with which they expel one pathogen (Cryptococcus) depending on the level of threat from a secondary viral infection.

scholarly journals Janus Kinase-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Lucas Walz ◽  
Avi J. Cohen ◽  
Andre P. Rebaza ◽  
James Vanchieri ◽  
Martin D. Slade ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Outcomes ◽  
Randomized Clinical Trials ◽  
Type I Interferon ◽  
Meta Analysis ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Jak Inhibitor ◽  
Jak Inhibitors

Background Novel coronavirus (SARS-CoV-2) has infected over 17 million. Novel therapies are urgently needed. Janus-kinase (JAK) inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and by their ability to promote viral clearance in past coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate role of these therapies in COVID-19 patients. Methods MEDLINE and MedRxiv were searched until July 30th, 2020, including studies that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clear risk estimates or those that permitted back-calculation. Results We searched 733 studies, ultimately including four randomized and eleven non-randomized clinical trials. JAK-inhibitor recipients had significantly reduced odds of mortality (OR, 0.12; 95%CI, 0.03-0.39, p=0.0005) and ICU admission (OR, 0.05; 95%CI, 0.01-0.26, p=0.0005), and had significantly increased odds of hospital discharge (OR, 22.76; 95%CI, 10.68-48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95%CI, 0.04-0.85, p=0.03), and increased odds of discharge bordering significance (OR, 1.89; 95%CI, 1.00-3.59, p=0.05). Conclusions JAK-inhibitor treatment is significantly associated with positive clinical outcomes regarding mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes regarding mortality and discharge. While these data show promise, additional randomized clinical trials are needed to further elucidate the efficacy of JAK-inhibitors and Type I interferons and clinical outcomes in COVID-19.

Interferon-α and -β inhibit the in vitro differentiation of immunocompetent human dendritic cells from CD14+ precursors

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 210-217 ◽  
Author(s):  
Bradford L. McRae ◽  
Taro Nagai ◽  
Roshanak Tolouei Semnani ◽  
Jean Maguire van Seventer ◽  
Gijs A. van Seventer
Keyword(s):  
T Cell ◽  
Type I Interferons ◽  
Interferon Α ◽  
Type I ◽  
Cell Secretion ◽  
Gm Csf ◽  
Th Cell ◽  
Acquired Immune Responses ◽  
And Function

Dendritic cell (DC) precursors and immature DC reside in epithelium where they encounter pathogens and cytokines, which stimulate their differentiation. We hypothesized that type-I interferons (IFN- and -β), cytokines that are produced early in the innate immune response against viruses and some bacteria, may influence DC differentiation and function. To examine this possibility, we used an in vitro model of DC differentiation in which initial culture of human CD14+monocytes with granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 generates immature DC, and subsequent culture with tumor necrosis factor (TNF)- drives the final development into mature DC. We found in this model that IFN-/β, added from the initiation of the culture on, significantly reduced the survival and altered the morphology and differentiation of DC. TNF-–dependent maturation of IFN-β–treated immature DC led to cells with reduced expression of CD1a, CD40, CD54, and CD80 when compared with mature DC controls. IFN-/β–treated DC further had a reduced capacity to induce naive Th-cell proliferation through allostimulation or anti-CD3 monoclonal antibody stimulation. In addition, IFN-/β–treated DC secreted less IL-12 upon stimulation with Staphylococcus aureus Cowan strain or with CD4+ T cells, and this decrease correlated directly with their inability to support CD4+ T-cell secretion of IFN-γ, even though T-cell lymphotoxin production was unaffected. These findings indicate that type-I IFNs can influence the generation of acquired immune responses by modifying T-helper cell differentiation through the regulation of DC differentiation and function.

scholarly journals Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA)

2008 ◽  
Vol 68 (9) ◽  
pp. 1486-1493 ◽  
Author(s):  
M F Roelofs ◽  
M H Wenink ◽  
F Brentano ◽  
S Abdollahi-Roodsaz ◽  
B Oppers-Walgreen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mrna Expression ◽  
Cytokine Production ◽  
Synovial Fibroblasts ◽  
Synovial Inflammation ◽  
Biologically Active ◽  
Type I Interferons ◽  
Interferon Α ◽  
Type I ◽  
Increased Risk

Background:Rheumatoid arthritis (RA) has been associated with an increased risk of infections, but the underlying pathways have not yet been identified. Toll-like receptors (TLR) probably play a role in synovial inflammation and may also contribute to the understanding of the role of infections in RA.Objectives:To investigate if the synovial expression of TLR3 and TLR7 in RA correlates with that of inflammatory cytokines, and to assess whether this has functional consequences for local cytokine production and to study potential links between the TLR3/7 axis and TLR4 in RA synovium.Methods:Immunohistochemistry was used to study the expression of TLR3, TLR7, interferon α (IFNα), tumour necrosis factor α (TNFα) and interleukins IL1β, IL12, IL17 and IL18 in RA synovium obtained by arthroscopy from 34 patients with RA. Monocytes, monocyte-derived dendritic cells (MoDCs) and RA synovial fibroblasts were stimulated via TLR3 (poly-IC) and TLR7 (loxorubin), after which IL1β, IL6 and TNFα were measured by Luminex bead array technology. Following preincubation with IFNα, IL1β and IL18, TLR3 and TLR7 mRNA expression was assessed using real-time PCR. Cytokine production after preincubation with IFNα and subsequent TLR stimulation was measured.Results:Synovial TLR3/7 expression was co-expressed with IFNα, IL1β and IL18, but not with TNFα, IL12 and IL17. Stimulation of TLR3/TLR7 on monocytes, MoDCs or synovial fibroblasts led to secretion of type I IFN but no biologically active IL1β or IL18 could be detected. Type I IFNα increased TLR3/7 mRNA expression whereas IL1β and IL18 did not. In spite of the fact that the mRNA level of TLR4 remained unchanged, IFNα enhanced the response to TLR4 agonists, a phenomenon that was clearly more marked in patients with RA.Conclusion:Type I interferons are highly co-expressed with TLR3/TLR7 in RA synovium. They enhance TLR3/TLR7-mediated cytokine production and also TLR4-mediated responses.

Sign in / Sign up

Export Citation Format

Share Document