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.

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.

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

2018 ◽  
Vol 10 (468) ◽  
pp. eaao2151 ◽  
Author(s):  
Hart S. Dengler ◽  
Xiumin Wu ◽  
Ivan Peng ◽  
Cornelia H. Rinderknecht ◽  
Youngsu Kwon ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Suppressive Effect ◽  
Therapeutic Benefit ◽  
Janus Kinase ◽  
Interleukin 4 ◽  
Type I ◽  
Lung Pathology ◽  
Corticosteroid Administration ◽  
Local Inhibition ◽  
Janus Kinase 1

Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, we hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, we synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Our data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.

scholarly journals Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) and Spike (S) Proteins Antagonize Host Type I Interferon Response

2021 ◽  
Vol 11 ◽  
Author(s):  
Qi Zhang ◽  
Zhiqiang Chen ◽  
Chenxiao Huang ◽  
Jiuyuan Sun ◽  
Minfei Xue ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Type I Interferon ◽  
Typical Feature ◽  
Janus Kinase ◽  
Interferon Response ◽  
Type I ◽  
Downstream Signaling ◽  
Janus Kinase 1

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide and has infected more than 250 million people. A typical feature of COVID-19 is the lack of type I interferon (IFN-I)-mediated antiviral immunity in patients. However, the detailed molecular mechanisms by which SARS-CoV-2 evades the IFN-I-mediated antiviral response remain elusive. Here, we performed a comprehensive screening and identified a set of SARS-CoV-2 proteins that antagonize the IFN-I response. Subsequently, we characterized the mechanisms of two viral proteins antagonize IFN-I production and downstream signaling. SARS-CoV-2 membrane protein binds to importin karyopherin subunit alpha-6 (KPNA6) to inhibit interferon regulatory factor 3(IRF3) nuclear translocation. Further, the spike protein interacts with signal transducer and activator of transcription 1 (STAT1) to block its association with Janus kinase 1 (JAK1). This study increases our understanding of SARS-CoV-2 pathogenesis and suggests novel therapeutic targets for the treatment of COVID-19.

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.

Signal transduction by the atopy-associated human thymic stromal lymphopoietin (TSLP) receptor depends on Janus kinase function

2010 ◽  
Vol 391 (2/3) ◽  
Author(s):  
Andreas Wohlmann ◽  
Katrin Sebastian ◽  
Andreas Borowski ◽  
Sebastian Krause ◽  
Karlheinz Friedrich
Keyword(s):  
Tyrosine Kinases ◽  
Inflammatory Responses ◽  
Thymic Stromal Lymphopoietin ◽  
Janus Kinase ◽  
Type I ◽  
Atopic Diseases ◽  
Receptor System ◽  
Α Subunit ◽  
Signal Transducers ◽  
Receptor Chain

Abstract Thymic stromal lymphopoietin (TSLP) is an interleukin-(IL)-7-like cytokine with emerging pathological importance for the development of atopic diseases such as allergic asthma bronchiale. The TSLP receptor (TSLPR), a heterodimeric type I cytokine receptor, shares the IL-7R α-subunit with the IL-7 receptor system. The specific TSLPR α-chain shows similarities with the γc receptor chain, but has some unusual features within the receptor family in both its ligand-binding and cytoplasmic domain. The murine TSLPR signals via the signal transducers and activators of transcription STAT5 and STAT3, but is unique among cytokine receptors in that it activates STATs without the involvement of Janus (JAK) tyrosine kinases, but instead utilizes the Src type kinase Tec. Here, we show by Western blotting and reporter gene experiments in combination with the application of a specific JAK inhibitor that the human TSLP receptor, in contrast, requires the function of JAK1 and JAK2 for STAT activation. Moreover, we demonstrate that the human TSLPR mediates gene regulation not only through STAT5 and STAT3 but has also the potential to mediate transcription via STAT1. Our work should help to understand more thoroughly how TSLP triggers inflammatory responses in the course of atopic diseases.

G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3305-3312 ◽  
Author(s):  
Quan-Sheng Zhu ◽  
Lisa J. Robinson ◽  
Vera Roginskaya ◽  
Seth J. Corey
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Myeloid Cell ◽  
Pi3 Kinase ◽  
Janus Kinase ◽  
Serine Phosphorylation ◽  
Myeloid Differentiation ◽  
Loss Of Function ◽  
Wild Type ◽  
In The Wild

Abstract The granulocyte colony-stimulating factor receptor (G-CSFR) transduces intracellular signals for myeloid cell proliferation, survival, and differentiation through the recruitment of nonreceptor protein tyrosine kinases Lyn and janus kinase 2 (Jak2). This results in the tyrosine phosphorylation of a small set of positive and negative adapters and effectors. Grb2-associated binder-2 (Gab2) is a newly described adapter molecule, preferentially expressed in hematopoietic cells and associated with phosphatidylinositol 3 (PI3) kinase. Studies suggest that Gab2 plays both positive and negative roles in cytokine receptor signaling. To investigate the role Gab2 plays in G-CSF receptor-mediated signaling, we have analyzed its activation state and correlated that with wild-type and mutant G-CSF receptors stably expressed in the murine factor-dependent Ba/F3 cell lines. G-CSF-induced tyrosine phosphorylation of Gab2 occurred in the wild-type and single Y-to-F mutants (Y704F, Y729F, and Y744F), but not in the ADA and W650R loss-of-function mutants. Cells expressing truncated proximal G-CSFR, the tyrosine-null (Y4F) G-CSFR, or Y764F mutant receptors had decreased phosphorylation of Gab2. Specific inhibitors of Src kinase (PD173 and PP1) but not Jak2 kinase (AG490) blocked Gab2 phosphorylation. Phosphorylation of Gab2 occurred in wild-type, but not Lyn-deficient, G-CSFR-transfected DT40 B cells. These data propose that Lyn, not Jak2, phosphorylates Gab2 and that maximal phosphorylation of Gab2 requires Y764, a Grb2-binding site. Serine phosphorylation of Akt, a marker of PI3-kinase activity, was detected in both wild-type and truncated proximal domain receptors, but not in the ADA and W650R mutants. Levels of phospho-Akt and phospho-extracellular signal-regulated kinase (phospho-ERK) were greater in proximal truncated than in wild-type G-CSFR cells, suggesting that Gab2 is dissociated from PI3 kinase or ERK activities. Overexpression of Gab2 enhanced the phosphorylation state of Akt, but not of ERK. This inhibited the proliferation of wild-type and truncated G-CSFR-transfected Ba/F3 cells and enhanced their myeloid differentiation. All together, these data indicate that G-CSF treatment leads to Lyn-mediated tyrosine phosphorylation of Gab2, which may serve as an important intermediate of enhanced Akt activity and myeloid differentiation, not growth/survival response. (Blood. 2004; 103:3305-3312)

scholarly journals Lung involvement in monogenic interferonopathies

2020 ◽  
Vol 29 (158) ◽  
pp. 200001
Author(s):  
Salvatore Cazzato ◽  
Alessia Omenetti ◽  
Claudia Ravaglia ◽  
Venerino Poletti
Keyword(s):  
Disease Onset ◽  
Interstitial Lung Diseases ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Lung Involvement ◽  
Target Organs ◽  
Janus Kinase 1 ◽  
Function Impairment ◽  
Organ Specific

Monogenic type I interferonopathies are inherited heterogeneous disorders characterised by early onset of systemic and organ specific inflammation, associated with constitutive activation of type I interferons (IFNs). In the last few years, several clinical reports identified the lung as one of the key target organs of IFN-mediated inflammation. The major pulmonary patterns described comprise children's interstitial lung diseases (including diffuse alveolar haemorrhages) and pulmonary arterial hypertension but diagnosis may be challenging. Respiratory symptoms may be either mild or absent at disease onset and variably associated with systemic or organ specific inflammation. In addition, associated extrapulmonary clinical features may precede lung function impairment by years, and patients may display severe/endstage lung involvement, although this may be clinically hidden during the long-term disease course. Conversely, a few cases of atypical severe lung involvement at onset have been reported without clinically manifested extrapulmonary signs. Hence, a multidisciplinary approach involving pulmonologists, paediatricians and rheumatologists should always be considered when a monogenic interferonopathy is suspected. Pulmonologists should also be aware of the main pattern of presentation to allow prompt diagnosis and a targeted therapeutic strategy. In this regard, promising therapeutic strategies rely on Janus kinase-1/2 (JAK-1/2) inhibitors blocking the type I IFN-mediated intracellular cascade.

scholarly journals Efficacy and Safety of Janus Kinase Inhibitors in Type I Interferon-Mediated Monogenic Autoinflammatory Disorders: A Scoping Review

2021 ◽  
Author(s):  
Pedro Jesús Gómez-Arias ◽  
Francisco Gómez-García ◽  
Jorge Hernández-Parada ◽  
Ana María Montilla-López ◽  
Juan Ruano ◽  
...  
Keyword(s):  
Scoping Review ◽  
Kinase Inhibitors ◽  
Type I Interferon ◽  
Janus Kinase ◽  
Type I ◽  
Efficacy And Safety ◽  
Autoinflammatory Disorders ◽  
Janus Kinase Inhibitors

scholarly journals FRI0136 PERIPHERAL PROTEIN BIOMARKER CHANGES FOLLOWING SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB IN ADULTS WITH MODERATELY-TO-SEVERELY ACTIVE RHEUMATOID ARTHRITIS WITH PRIOR INADEQUATE RESPONSE TO METHOTREXATE (FINCH1)

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 650.2-651
Author(s):  
P. C. Taylor ◽  
E. Elboudwarej ◽  
B. Downie ◽  
J. Liu ◽  
R. E. Hawtin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Migration ◽  
Active Rheumatoid Arthritis ◽  
Immune Cell ◽  
Janus Kinase ◽  
Inadequate Response ◽  
Bone Biology ◽  
Janus Kinase 1 ◽  
Immune Cell Migration ◽  
Dose Dependent

Background:Filgotinib (FIL), an oral selective Janus kinase 1 (JAK1) inhibitor has shown efficacy and safety in multiple phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA), including those with prior inadequate response to methotrexate (MTX) therapy (FINCH1;NCT02889796).Objectives:A longitudinal study of protein biomarkers related to JAK signaling1, bone biology2, immune cell migration2, and inflammation2was conducted to identify RA-associated markers altered by FIL vs MTX or adalimumab (ADA).Methods:FINCH1 RA patients (pts) were randomized to receive either a stable dose of MTX with placebo (PBO+MTX), ADA+MTX, and either FIL100mg+MTX or FIL200mg+MTX, once daily. Plasma, serum, and urine samples were taken from a subset of pts (~548) at baseline (BL) and weeks (wks) 4 and 12. Twenty-six pre-defined cytokines (biomarkers) were evaluated using ELISA. BL correlation between biomarkers and clinical response measures (DAS28CRP, SJC28, TJC28, CDAI, Patient Assessment and FACIT), were analyzed by Spearman Rank. Multiscale bootstrap resampling evaluated significant intra-cluster biomarker membership. Mean changes in biomarker levels from BL to wks 4 and 12 were compared between arms using PBO-adjusted estimates from a linear mixed effects model. A 5% false-discovery rate was applied for all analyses.Results:At BL, distinct biomarker-based pt clusters (CL) were identified. The strongest intra-group correlations were in bone-cartilage resorption/inflammation (CL1; Rho range 0.37–0.88) and JAK activity (CL2; Rho range 0.41–0.71). Individual BL cytokine levels were significantly associated with DAS28CRP, with unique biomarkers specific to various subcomponents of the score. Eleven biomarkers were associated with DAS28CRP, while 5, 3, and 2 were associated with CDAI, SJC28, and TJC28, respectively. The magnitude of FIL-associated treatment effects was time- and dose-dependent. Significant biomarker changes from BL were observed in FIL pts, relative to PBO+MTX pts. FIL100mg+MTX led to a significant change in 8 biomarkers by either 4 or 12 wks of treatment; FIL200mg+MTX significantly changed these and an additional 4 biomarkers by either time point. The greatest effect of FIL200mg+MTX was at 12 wks for CXCL13 (-38.4%) and IL6 (-53.7%). All treatment arms led to significant reductions in TNFα relative to PBO+MTX. FIL200mg+MTX treatment led to larger reductions of TNFα than ADA+MTX treatment at both wk4 (-24.7% vs -17.9%) and wk12 (-20.5% vs -12.2%), although the differences were not statistically significant.FIL and ADA caused differential patterns of cytokine response at either wks 4 or 12. Of 12 biomarkers with a significant FIL200mg+MTX treatment effect, there was a significantly larger reduction in TNFSF13B and CTX1 relative to ADA+MTX at 12 wks. Of 8 biomarkers with FIL100mg+MTX effects, only 2 (CXCL10 at wk 4; CXCL13 at wks 4 and 12) had significant differences from ADA+MTX. Relative either to FIL200mg+MTX or FIL100mg+MTX, and despite the same direction of effect, ADA+MTX led to a significantly larger reduction in CCL2, CXCL10, CCL4, and CXCL13.Conclusion:Compared with PBO, 12 wks of FIL treatment significantly reduced cytokines associated with JAK activity1, bone biology2, inflammation2, and immune cell migration2in MTX-IR pts. The effects were largely FIL dose-dependent; most cytokines exhibited similar effects regardless of treatment arms, but differential changes between FIL+MTX and ADA+MTX were observed, supportive of the different mechanisms of action of these therapies.References:[1]Majoros A, et al. Front Immunol. 2017;8:29[2]Brennan F, and McInnes I. J Clin Invest. 2008;118:3537-45Acknowledgments:This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc.Disclosure of Interests:Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Emon Elboudwarej Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Bryan Downie Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc.

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