scholarly journals Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK/STAT Signaling

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 899 ◽  
Author(s):  
Justin A. Roby ◽  
Katharina Esser-Nobis ◽  
Elyse C. Dewey-Verstelle ◽  
Marian R. Fairgrieve ◽  
Johannes Schwerk ◽  
...  
Keyword(s):  
Nonstructural Protein ◽  
Heat Shock Protein 90 ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Critical Determinant ◽  
Wide Range ◽  
Stat Signaling ◽  
Virus West Nile ◽  
Flavivirus Infection ◽  
Stat Pathway

Pathogenic flaviviruses antagonize host cell Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling downstream of interferons α/β. Here, we show that flaviviruses inhibit JAK/STAT signaling induced by a wide range of cytokines beyond interferon, including interleukins. This broad inhibition was mapped to viral nonstructural protein 5 (NS5) binding to cellular heat shock protein 90 (HSP90), resulting in reduced Janus kinase–HSP90 interaction and thus destabilization of unchaperoned JAKs (and other kinase clients) of HSP90 during infection by Zika virus, West Nile virus, and Japanese encephalitis virus. Our studies implicate viral dysregulation of HSP90 and the JAK/STAT pathway as a critical determinant of cytokine signaling control during flavivirus infection.

scholarly journals The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4000
Author(s):  
Esra’a Keewan ◽  
Ksenia Matlawska-Wasowska
Keyword(s):  
Intracellular Signaling ◽  
Cell Communication ◽  
Janus Kinase ◽  
Signaling Cascades ◽  
Cytokine Signaling ◽  
Surface Receptors ◽  
Wide Range ◽  
Stat Signaling ◽  
Leukemia Development

Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.

scholarly journals An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components

2019 ◽  
Author(s):  
Wai Hoong Chang ◽  
Alvina G. Lai
Keyword(s):  
Genetic Alterations ◽  
Janus Kinase ◽  
Renal Tumors ◽  
Molecular Features ◽  
Wide Range ◽  
Stat Signaling ◽  
Cancer Types ◽  
Endometrial Cancers ◽  
Pan Cancer ◽  
Stat Pathway

Since its discovery almost three decades ago, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has paved the road for understanding inflammatory and immunity processes related to a wide range of human pathologies including cancer. Several studies have demonstrated the importance of JAK-STAT pathway components in regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood. Focusing on 133 genes involved in JAK-STAT signaling, we found that copy number alterations underpin transcriptional dysregulation that differs within and between cancer types. Integrated analyses on over 18,000 tumors representing 21 cancer types revealed a core set of 28 JAK-STAT pathway genes that correlated with survival outcomes in brain, renal, lung and endometrial cancers. High JAK-STAT scores were associated with increased mortality rates in brain and renal cancers, but not in lung and endometrial cancers where hyperactive JAK-STAT signaling is a positive prognostic factor. Patients with aberrant JAK-STAT signaling demon-strated pan-cancer molecular features associated with misex-pression of genes in other oncogenic pathways (Wnt, MAPK, TGF-β, PPAR and VEGF). Brain and renal tumors with hyperactive JAK-STAT signaling had increased regulatory T cell gene (Treg) expression. A combined model uniting JAK-STAT and Tregs allowed further delineation of risk groups where patients with high JAK-STAT and Treg scores consistently performed the worst. Providing a pan-cancer perspective of clinically-relevant JAK-STAT alterations, this study could serve as a framework for future research investigating anti-tumor immunity using combination therapy involving JAK-STAT and immune checkpoint inhibitors.

scholarly journals Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Maaria Palmroth ◽  
Krista Kuuliala ◽  
Ritva Peltomaa ◽  
Anniina Virtanen ◽  
Antti Kuuliala ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Treatment Response ◽  
Peripheral Blood ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Stat3 Phosphorylation ◽  
Stat Pathway

ObjectiveCurrent knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA.MethodsSixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated.ResultsTofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-γ-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.ConclusionsTofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.

scholarly journals SOCS1/SOCS3 Immune Axis Modulates Synthetic Perturbations in IL6 Biological Circuit for Dynamical Cellular Response

2020 ◽  
Author(s):  
Bhavnita Soni ◽  
Shailza Singh
Keyword(s):  
Signaling Pathway ◽  
Cellular Response ◽  
Inflammatory Cytokine ◽  
Cytokine Expression ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Macrophage Phenotype ◽  
Regulatory Circuit ◽  
Stat Pathway

AbstractMacrophage phenotype plays a crucial role in the pathogenesis of Leishmanial infection. Pro-inflammatory cytokines are the key regulators that eliminate the infection induced by Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Suppressor of cytokine signaling (SOCS) is a well-known negative feedback regulator of JAK/STAT pathway. However, change in expression levels of SOCS in correlation with the establishment of infection is not well understood. Mathematical modeling of IL6 signaling pathway have helped identified the role of SOCS1 in establishment of infection. Furthermore, the ratio of SOCS1 and SOCS3 has been quantified both in silico as well as in vitro, indicating an immune axis which governs the macrophage phenotype during L. major infection. The ability of SOCS1 protein to inhibit the JAK/STAT1 signaling pathway and thereby decreasing pro-inflammatory cytokine expression makes it a strong candidate for therapeutic intervention. Using synthetic biology approaches, peptide based immuno-regulatory circuit have been designed to target the activity of SOCS1 which can restore pro-inflammatory cytokine expression during infection.

Atomistic insight into the inhibition mechanisms of suppressors of cytokine signaling on Janus kinase

2019 ◽  
Vol 21 (24) ◽  
pp. 12905-12915 ◽  
Author(s):  
Yaru Wei ◽  
Zhiyang Zhang ◽  
Nai She ◽  
Xin Chen ◽  
Yuan Zhao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Negative Feedback ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Jak Kinase ◽  
Stat Signaling ◽  
Suppressors Of Cytokine Signaling ◽  
Insight Into

Suppressors of cytokine signaling (SOCS) act as negative feedback regulators of the Janus kinase/signal transducer (JAK–STAT) signaling pathway by inhibiting the activity of JAK kinase.

scholarly journals Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 977 ◽  
Author(s):  
Ethan L. Morgan ◽  
Andrew Macdonald
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
Significant Proportion ◽  
Human Papillomaviruses ◽  
Janus Kinase ◽  
Signalling Pathways ◽  
Proliferative Potential ◽  
Promote Cell Proliferation ◽  
Wide Range ◽  
Stat Pathway

Human papillomaviruses (HPVs) are small, DNA viruses that cause around 5% of all cancers in humans, including almost all cervical cancer cases and a significant proportion of anogenital and oral cancers. The HPV oncoproteins E5, E6 and E7 manipulate cellular signalling pathways to evade the immune response and promote virus persistence. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has emerged as a key mediator in a wide range of important biological signalling pathways, including cell proliferation, cell survival and the immune response. While STAT1 and STAT2 primarily drive immune signalling initiated by interferons, STAT3 and STAT5 have widely been linked to the survival and proliferative potential of a number of cancers. As such, the inhibition of STAT3 and STAT5 may offer a therapeutic benefit in HPV-associated cancers. In this review, we will discuss how HPV manipulates JAK/STAT signalling to evade the immune system and promote cell proliferation, enabling viral persistence and driving cancer development. We also discuss approaches to inhibit the JAK/STAT pathway and how these could potentially be used in the treatment of HPV-associated disease.

Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

2016 ◽  
Vol 26 (1) ◽  
Author(s):  
Amira Alkharusi ◽  
Mercedes Mirecki-Garrido ◽  
Zuheng Ma ◽  
Fahad Zadjali ◽  
Amilcar Flores-Morales ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Type I ◽  
Suppressor Of Cytokine Signaling ◽  
Β Cell ◽  
Diabetes In Mice ◽  
Socs Proteins ◽  
Stat Pathway

AbstractDiabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity.The elevated sensitivity of SOCS2We show that 6-month-old SOCS2Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy, and which is protective against MLDSTZ-induced type I diabetes in mice. SOCS2-dependent control of β-cell survival may be of relevance to islet regeneration and survival in transplantation.

scholarly journals Identification of Residues Critical for the Interferon Antagonist Function of Langat Virus NS5 Reveals a Role for the RNA-Dependent RNA Polymerase Domain

2007 ◽  
Vol 81 (13) ◽  
pp. 6936-6946 ◽  
Author(s):  
Gregory S. Park ◽  
Keely L. Morris ◽  
Roselyn G. Hallett ◽  
Marshall E. Bloom ◽  
Sonja M. Best
Keyword(s):  
Amino Acids ◽  
Rna Polymerase ◽  
Nonstructural Protein ◽  
Encephalitis Virus ◽  
Janus Kinase ◽  
Amino Acid Residues ◽  
Rna Dependent Rna Polymerase ◽  
Stat Signaling ◽  
Langat Virus ◽  
Tick Borne Encephalitis Virus

ABSTRACT All pathogenic flaviviruses examined thus far inhibit host interferon (IFN) responses by suppressing the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Both Langat virus (LGTV; a member of the tick-borne encephalitis virus serogroup) and Japanese encephalitis virus use the nonstructural protein NS5 to suppress JAK-STAT signaling. However, NS5 is also critical to virus replication, contributing methyltransferase and RNA-dependent RNA polymerase (RdRP) activities. The specific amino acid residues of NS5 involved in IFN antagonism are not known. Here, we demonstrate that the LGTV NS5 JAK-STAT inhibitory domain is contained between amino acids 355 and 735 (of 903), a range which lies within the RdRP domain. Furthermore, we identified two noncontiguous stretches of specific amino acids within the RdRP, 374 to 380 and 624 to 647, as critical for inhibition of JAK-STAT signaling. Despite considerable separation on the linear NS5 sequence, these residues localized adjacent to each other when modeled on the West Nile virus RdRP crystal structure. Due to the general conservation of RdRP structures, these results suggest that the specific residues identified act cooperatively to form a unique functional site on the RdRP responsible for JAK-STAT inhibition. This insight into the mechanism underlying flavivirus IFN evasion strategies will facilitate the design of antiviral therapeutics that potentiate the action of IFN during infection.

scholarly journals Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies

2012 ◽  
Vol 30 (9) ◽  
pp. 1005-1014 ◽  
Author(s):  
Pasquale Sansone ◽  
Jacqueline Bromberg
Keyword(s):  
Interleukin 6 ◽  
Potential Role ◽  
Tumor Formation ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Metastatic Progression ◽  
And Function ◽  
Principal Pathway ◽  
Stat Pathway

The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6–mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers.

scholarly journals The use of Drosophila Melanogaster as a Model Organism to study the effect of Innate Immunity on Metabolism

2020 ◽  
Author(s):  
Abeer Mohbeddin ◽  
Nawar Haj Ahmed ◽  
Layla Kamareddine
Keyword(s):  
Drosophila Melanogaster ◽  
Fat Body ◽  
Model Organism ◽  
Fruit Fly ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Metabolic Homeostasis ◽  
Stat Signaling ◽  
Stat Pathway

Apart from its traditional role in disease control, recent body of evidence has implicated a role of the immune system in regulating metabolic homeostasis. Owing to the importance of this “immune-metabolic alignment” in dictating a state of health or disease, a proper mechanistic understanding of this alignment is crucial in opening up for promising therapeutic approaches against a broad range of chronic, metabolic, and inflammatory disorders like obesity, diabetes, and inflammatory bowel syndrome. In this project, we addressed the role of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) innate immune pathway in regulating different metabolic parameters using the Drosophila melanogaster (DM) fruit fly model organism. Mutant JAK/STAT pathway flies with a systemic knockdown of either Domeless (Dome) [domeG0282], the receptor that activates JAK/STAT signaling, or the signal-transducer and activator of transcription protein at 92E (Stat92E) [stat92EEY10528], were used. The results of the study revealed that blocking JAK/STAT signaling alters the metabolic profile of mutant flies. Both domeG0282 and stat92EEY10528 mutants had an increase in body weight, lipid deprivation from their fat body (lipid storage organ in flies), irregular accumulation of lipid droplets in the gut, systemic elevation of glucose and triglyceride levels, and differential down-regulation in the relative gene expression of different peptide hormones (Tachykinin, Allatostatin C, and Diuretic hormone 31) known to regulate metabolic homeostasis in flies. Because the JAK/STAT pathway is evolutionary conserved between invertebrates and vertebrates, our potential findings in the fruit fly serves as a platform for further immune-metabolic translational studies in more complex mammalian systems including humans.

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