scholarly journals Emerging Connections of S1P-Metabolizing Enzymes with Host Defense and Immunity During Virus Infections

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1097 ◽  
Author(s):  
Jennifer J. Wolf ◽  
Caleb J. Studstill ◽  
Bumsuk Hahm
Keyword(s):  
Therapeutic Option ◽  
Sphingosine Kinase ◽  
Type I ◽  
Virus Infections ◽  
Metabolizing Enzymes ◽  
Host Interactions ◽  
Vital Functions ◽  
Sphingosine 1 Phosphate ◽  
Antiviral Activities ◽  
S1p Lyase

The sphingosine 1-phosphate (S1P) metabolic pathway is a dynamic regulator of multiple cellular and disease processes. Identification of the immune regulatory role of the sphingosine analog FTY720 led to the development of the first oral therapy for the treatment of an autoimmune disease, multiple sclerosis. Furthermore, inhibitors of sphingosine kinase (SphK), which mediate S1P synthesis, are being evaluated as a therapeutic option for the treatment of cancer. In conjunction with these captivating discoveries, S1P and S1P-metabolizing enzymes have been revealed to display vital functions during virus infections. For example, S1P lyase, which is known for metabolizing S1P, inhibits influenza virus replication by promoting antiviral type I interferon innate immune responses. In addition, both isoforms of sphingosine kinase have been shown to regulate the replication or pathogenicity of many viruses. Pro- or antiviral activities of S1P-metabolizing enzymes appear to be dependent on diverse virus–host interactions and viral pathogenesis. This review places an emphasis on summarizing the functions of S1P-metabolizing enzymes during virus infections and discusses the opportunities for designing pioneering antiviral drugs by targeting these host enzymes.

scholarly journals Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

2018 ◽  
Vol 51 (5) ◽  
pp. 2377-2396 ◽  
Author(s):  
Shi-fang Li ◽  
Mei-jiao Gong ◽  
Fu-rong Zhao ◽  
Jun-jun Shao ◽  
Yin-li Xie ◽  
...  
Keyword(s):  
Biological Activities ◽  
Therapeutic Option ◽  
Influenza Viruses ◽  
Type I Interferons ◽  
Type I ◽  
Virus Infections ◽  
Type I Ifns ◽  
Immunodeficiency Virus ◽  
Potential Applications ◽  
Antiviral Activities

The interferons (IFNs) are a primary defense against pathogens because of the strong antiviral activities they induce. IFNs can be classified into three groups: type I, type II and type III, according to their genetic, structural, and functional characteristics and their receptors on the cell surface. The type I IFNs are the largest group and include IFN-α, IFN-β, IFN-ε, IFN-ω, IFN-κ, IFN-δ, IFN-τ and IFN-ζ. The use of IFNs for the treatment of viral infectious diseases on their antiviral activity may become an important therapeutic option, for example, IFN-α is well known for the successful treatment of hepatitis B and C virus infections, and interest is increasing in the antiviral efficacy of other novel IFN classes and their potential applications. Therefore, in this review, we summarize the recent progress in the study of the biological activities of all the type I IFN classes and their potential applications in the treatment of infections with immunodeficiency virus, hepatitis viruses, and influenza viruses.

scholarly journals An Integrated View of Deubiquitinating Enzymes Involved in Type I Interferon Signaling, Host Defense and Antiviral Activities

2021 ◽  
Vol 12 ◽  
Author(s):  
Guanghui Qian ◽  
Liyan Zhu ◽  
Gen Li ◽  
Ying Liu ◽  
Zimu Zhang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Host Defense ◽  
Critical Role ◽  
Innate Immune ◽  
Type I Interferons ◽  
Future Perspective ◽  
Type I ◽  
Virus Infections ◽  
Deubiquitinating Enzymes ◽  
Antiviral Activities

Viral infectious diseases pose a great challenge to human health around the world. Type I interferons (IFN-Is) function as the first line of host defense and thus play critical roles during virus infection by mediating the transcriptional induction of hundreds of genes. Nevertheless, overactive cytokine immune responses also cause autoimmune diseases, and thus, tight regulation of the innate immune response is needed to achieve viral clearance without causing excessive immune responses. Emerging studies have recently uncovered that the ubiquitin system, particularly deubiquitinating enzymes (DUBs), plays a critical role in regulating innate immune responses. In this review, we highlight recent advances on the diverse mechanisms of human DUBs implicated in IFN-I signaling. These DUBs function dynamically to calibrate host defenses against various virus infections by targeting hub proteins in the IFN-I signaling transduction pathway. We also present a future perspective on the roles of DUB-substrate interaction networks in innate antiviral activities, discuss the promises and challenges of DUB-based drug development, and identify the open questions that remain to be clarified. Our review provides a comprehensive description of DUBs, particularly their differential mechanisms that have evolved in the host to regulate IFN-I-signaling-mediated antiviral responses.

scholarly journals Downregulation of Lipid Phosphate Phosphatase 3 correlates with Tumor-Infiltrating Immune Cells in Oral Cancer

2021 ◽  
Author(s):  
Supriya Vishwakarma ◽  
Deepti Joshi ◽  
Ritu Pandey ◽  
Saikat Das ◽  
Sramana Mukhopadhyay ◽  
...  
Keyword(s):  
Normal Mucosa ◽  
Tnm Staging ◽  
Metabolizing Enzymes ◽  
Normal Oral Mucosa ◽  
Lipid Phosphatases ◽  
Tumor Tissues ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
Lipid Phosphate ◽  
S1p Lyase

Abstract Purpose Sphingosine-1-phosphate (S1P), a potent oncogenic lipid. Intracellular levels of S1P are tightly regulated by eight S1P metabolizing enzymes. S1P is synthesized by phosphorylation of sphingosine which is catalyzed by two sphingosine kinases (SphK1 and SphK2). Five lipid phosphatases (two S1P phosphatases and three lipid phosphate phosphatases) reversibly convert S1P back to sphingosine. S1P is ultimately irreversibly degraded by S1P lyase. The role of sphingosine-1-phosphate (S1P) metabolizing enzymes in oral squamous cell carcinoma (OSCC) has not been fully studied. Methods In the current study, we have determined the protein expression of four S1P metabolizing enzymes, namely sphingosine Kinase (SphK) -1, SphK2, S1P phosphatase 1 (SGPP1), and lipid phosphate phosphatase 3 (LPP3) by immunohistochemistry (IHC) and western botting in tumor tissues of 46 OSCC patients and normal oral mucosa (N = 6). Further, we determined the associations of expression of S1P metabolizing enzymes with clinicopathological features of OSCC patients. Results SphK2 and LPP3 exhibit low IRS in OSCC tumors. Importantly, expression of SphK2 and LPP3 was downregulated in malignant cells compared to non-malignant mucosa. Further, LPP3 expression negatively correlated with TNM staging of patients (ρ = -0.307, p = 0.043). Importantly, TCGA analysis revealed that LPP3 expression was positively correlated with infiltration of B cells, neutrophils, macrophages, and dendritic cells in the HNSCC tumors. Conclusion In conclusion, our data show that expression of SphK2 and LPP3 is decreased in OSCC tumors compared to normal mucosa. Thus, LPP3 could represent a potential prognostic marker and therapeutic target for OSCC.

scholarly journals Products by the sphingosine kinase/sphingosine 1-phosphate (S1P) lyase pathway but not S1P stimulate mitogenesis

2005 ◽  
Vol 10 (6) ◽  
pp. 605-615 ◽  
Author(s):  
Yuki Kariya ◽  
Akio Kihara ◽  
Mika Ikeda ◽  
Fumiaki Kikuchi ◽  
Seiichi Nakamura ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Sphingosine 1 Phosphate ◽  
S1p Lyase

scholarly journals Sphingosine 1-phosphate turnover (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Nigel J Pyne ◽  
Susan Pyne
Keyword(s):  
Sphingosine Kinase ◽  
G Protein Coupled Receptors ◽  
Major Focus ◽  
Recessive Mutations ◽  
Sphingosine 1 Phosphate ◽  
Insufficiency Syndrome ◽  
S1p Lyase ◽  
G Protein Coupled ◽  
Intracellular Targets ◽  
Synthesis And Degradation

S1P (sphingosine 1-phosphate) is a bioactive lipid which, after release from cells via certain transporters, acts as a ligand for a family of five S1P-specific G protein-coupled receptors (S1P1-5). However, it also has a number of intracellular targets. S1P is formed by the ATP-dependent phosphorylation of sphingosine, catalysed by two isoforms of sphingosine kinase (EC 2.7.1.91). It can be dephosphorylated back to sphingosine by sphingosine 1-phosphate phosphatase (EC 3.1.3) or cleaved into phosphoethanolamine and hexadecenal by sphingosine 1-phosphate lyase (EC 4.1.2.27). Recessive mutations in the S1P lyase (SPL) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS). In general, S1P promotes cell survival, proliferation, migration, adhesion and inhibition of apoptosis. Intracellular S1P affects epigenetic regulation, endosomal processing, mitochondrial function and cell proliferation/senescence. S1P has myriad physiological functions, including vascular development, lymphocyte trafficking and neurogenesis. However, S1P is also involved in a number of diseases such as cancer, inflammation and fibrosis. Therefore, its GPCRs and enzymes of synthesis and degradation are a major focus for drug discovery.

Therapeutic Exploitation of Viral Interference

2020 ◽  
Vol 20 (4) ◽  
pp. 423-432 ◽  
Author(s):  
Imre Kovesdi ◽  
Tibor Bakacs
Keyword(s):  
Broad Spectrum ◽  
Viral Infections ◽  
Viral Vector ◽  
Antiviral Treatment ◽  
Type I ◽  
Virus Infections ◽  
Emerging Viruses ◽  
Viral Interference ◽  
Pathogenic Virus ◽  
Hepatitis C Rna

: Viral interference, originally, referred to a state of temporary immunity, is a state whereby infection with a virus limits replication or production of a second infecting virus. However, replication of a second virus could also be dominant over the first virus. In fact, dominance can alternate between the two viruses. Expression of type I interferon genes is many times upregulated in infected epithelial cells. Since the interferon system can control most, if not all, virus infections in the absence of adaptive immunity, it was proposed that viral induction of a nonspecific localized temporary state of immunity may provide a strategy to control viral infections. Clinical observations also support such a theory, which gave credence to the development of superinfection therapy (SIT). SIT is an innovative therapeutic approach where a non-pathogenic virus is used to infect patients harboring a pathogenic virus. : For the functional cure of persistent viral infections and for the development of broad- spectrum antivirals against emerging viruses a paradigm shift was recently proposed. Instead of the virus, the therapy should be directed at the host. Such a host-directed-therapy (HDT) strategy could be the activation of endogenous innate immune response via toll-like receptors (TLRs). Superinfection therapy is such a host-directed-therapy, which has been validated in patients infected with two completely different viruses, the hepatitis B (DNA), and hepatitis C (RNA) viruses. SIT exerts post-infection interference via the constant presence of an attenuated non-pathogenic avian double- stranded (ds) RNA viral vector which boosts the endogenous innate (IFN) response. SIT could, therefore, be developed into a biological platform for a new “one drug, multiple bugs” broad-spectrum antiviral treatment approach.

Apoptotic cell extrusion depends on single-cell synthesis of sphingosine-1-phosphate by sphingosine kinase 2

2021 ◽  
Vol 1866 (4) ◽  
pp. 158888
Author(s):  
Bruno Jaime Santacreu ◽  
Daniela Judith Romero ◽  
Lucila Gisele Pescio ◽  
Estefanía Tarallo ◽  
Norma Beatriz Sterin-Speziale ◽  
...  
Keyword(s):  
Single Cell ◽  
Apoptotic Cell ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
Cell Synthesis ◽  
Cell Extrusion

Altered Expression of Sphingosine-1-Phosphate Metabolizing Enzymes in Oral Cancer Correlate With Clinicopathological Attributes

2017 ◽  
Vol 35 (2) ◽  
pp. 139-141 ◽  
Author(s):  
Supriya Vishwakarma ◽  
Rahul Agarwal ◽  
Sudhir K. Goel ◽  
Rajendra K. Panday ◽  
Renu Singh ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Metabolizing Enzymes ◽  
Altered Expression ◽  
Sphingosine 1 Phosphate
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