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fredag 5 juli 2019

Ubikitini, Deubikitinaasit ja Herpes

https://www.ncbi.nlm.nih.gov/pubmed/?term=HERPES%2C+deubiquitinase

Search results

Items: 13

1.
Yuan H, You J, You H, Zheng C.
J Virol. 2018 Sep 12;92(19). pii: e01161-18. doi: 10.1128/JVI.01161-18. Print 2018 Oct 1.
HSV-1; IFNAR2; UL36USP; type I IFN-mediated signaling
Free PMC Article
2.
Bhattacharya S, Chakraborty D, Basu M, Ghosh MK.
Signal Transduct Target Ther. 2018 Jun 29;3:17. doi: 10.1038/s41392-018-0012-y. eCollection 2018.
Herpesvirus-associated ubiquitin-specific protease (HAUSP) is a USP family deubiquitinase. HAUSP is a protein of immense biological importance as it is involved in several cellular processes, including host-virus interactions, oncogenesis and tumor suppression, DNA damage and repair processes, DNA dynamics and epigenetic modulations, regulation of gene expression and protein function, spatio-temporal distribution, and immune functions. Since its discovery in the late 1990s as a protein interacting with a herpes virus regulatory protein, extensive studies have assessed its complex roles in p53-MDM2-related networks, identified numerous additional interacting partners, and elucidated the different roles of HAUSP in the context of cancer, development, and metabolic and neurological pathologies. Recent analyses have provided new insights into its biochemical and functional dynamics. In this review, we provide a comprehensive account of our current knowledge about emerging insights into HAUSP in physiology and diseases, which shed light on fundamental biological questions and promise to provide a potential target for therapeutic intervention.Free PMC Article
3.
Cai J, Chen HY, Peng SJ, Meng JL, Wang Y, Zhou Y, Qian XP, Sun XY, Pang XW, Zhang Y, Zhang J.
FASEB J. 2018 Oct;32(10):5238-5249. doi: 10.1096/fj.201700473RR. Epub 2018 Apr 24.
Ubiquitination and deubiquitination are important post-translational regulatory mechanisms responsible for fine tuning the antiviral signaling. In this study, we identified a deubiquitinase, the ubiquitin-specific peptidase 7/herpes virus associated ubiquitin-specific protease (USP7/HAUSP) as an important negative modulator of virus-induced signaling. Overexpression of USP7 suppressed Sendai virus and polyinosinic-polycytidylic acid and poly(deoxyadenylic-deoxythymidylic)-induced ISRE and IFN-β activation, and enhanced virus replication. Knockdown or knockout of endogenous USP7 expression had the opposite effect. Coimmunoprecipitation assays showed that USP7 physically interacted with tripartite motif (TRIM)27. This interaction was enhanced after SeV infection. In addition, TNF receptor-associated factor family member-associated NF-kappa-B-binding kinase (TBK)-1 was pulled down in the TRIM27-USP7 complex. Overexpression of USP7 promoted the ubiquitination and degradation of TBK1 through promoting the stability of TRIM27. Knockout of endogenous USP7 led to enhanced TRIM27 degradation and reduced TBK1 ubiquitination and degradation, resulting in enhanced type I IFN signaling. Our findings suggest that USP7 acts as a negative regulator in antiviral signaling by stabilizing TRIM27 and promoting the degradation of TBK1.-Cai, J., Chen, H.-Y., Peng, S.-J., Meng, J.-L., Wang, Y., Zhou, Y., Qian, X.-P., Sun, X.-Y., Pang, X.-W., Zhang, Y., Zhang, J. USP7-TRIM27 axis negatively modulates antiviral type I IFN signaling.
4.
Dong X, Guan J, Zheng C, Zheng X.
J Biol Chem. 2017 May 19;292(20):8472-8483. doi: 10.1074/jbc.M117.778076. Epub 2017 Mar 27.
Abstract. Herpes simplex virus 1 (HSV-1) infection manipulates distinct host DNA-damage responses to facilitate virus proliferation, but the molecular mechanisms remain to be elucidated. One possible HSV-1 target might be DNA damage-tolerance mechanisms, such as the translesion synthesis (TLS) pathway. In TLS, proliferating cell nuclear antigen (PCNA) is monoubiquitinated in response to DNA damage-caused replication fork stalling. Ubiquitinated PCNA then facilitates the error-prone DNA polymerase η (polη)-mediated TLS, allowing the fork to bypass damaged sites. Because of the involvement of PCNA ubiquitination in DNA-damage repair, we hypothesized that the function of PCNA might be altered by HSV-1. Here we show that PCNA is a substrate of the HSV-1 deubiquitinase UL36USP, which has previously been shown to be involved mainly in virus uptake and maturation. In HSV-1-infected cells, viral infection-associated UL36USP consistently reduced PCNA ubiquitination. The deubiquitination of PCNA inhibited the formation of polη foci and also increased cell sensitivity to DNA-damage agents. Moreover, the catalytically inactive mutant UL36C40A failed to deubiquitinate PCNA. Of note, the levels of virus marker genes increased strikingly in cells infected with wild-type HSV-1, but only moderately in UL36C40A mutant virus-infected cells, indicating that the UL36USP deubiquitinating activity supports HSV-1 virus replication during infection. These findings suggest a role of UL36USP in the DNA damage-response pathway.© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. KEYWORDS: DNA damage response; DNA polymerase; UL36USP; deubiquitylation (deubiquitination); herpesvirus; proliferating cell nuclear antigen (PCNA); translesion synthesis DOI: 10.1074/jbc.M117.778076
Free PMC Article
5.
Ye R, Su C, Xu H, Zheng C.
J Virol. 2017 Feb 14;91(5). pii: e02417-16. doi: 10.1128/JVI.02417-16. Print 2017 Mar 1.
The DNA sensing pathway triggers innate immune responses against DNA virus infection, and NF-κB signaling plays a critical role in establishing innate immunity. We report here that the herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP), which is a deubiquitinase (DUB), antagonizes NF-κB activation, depending on its DUB activity. In this study, ectopically expressed UL36USP blocked promoter activation of beta interferon (IFN-β) and NF-κB induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). UL36USP restricted NF-κB activation mediated by overexpression of STING, TANK-binding kinase 1, IκB kinase α (IKKα), and IKKβ, but not p65. UL36USP was also shown to inhibit IFN-stimulatory DNA-induced IFN-β and NF-κB activation under conditions of HSV-1 infection. Furthermore, UL36USP was demonstrated to deubiquitinate IκBα and restrict its degradation and, finally, abrogate NF-κB activation. More importantly, the recombinant HSV-1 lacking UL36USP DUB activity, denoted as C40A mutant HSV-1, failed to cleave polyubiquitin chains on IκBα. For the first time, UL36USP was shown to dampen NF-κB activation in the DNA sensing signal pathway to evade host antiviral innate immunity.IMPORTANCE It has been reported that double-stranded-DNA-mediated NF-κB activation is critical for host antiviral responses. Viruses have established various strategies to evade the innate immune system. The N terminus of the HSV-1 UL36 gene-encoded protein contains the DUB domain and is conserved across all herpesviruses. This study demonstrates that UL36USP abrogates NF-κB activation by cleaving polyubiquitin chains from IκBα and therefore restricts proteasome-dependent degradation of IκBα and that DUB activity is indispensable for this process. This study expands our understanding of the mechanisms utilized by HSV-1 to evade the host antiviral innate immune defense induced by NF-κB signaling.
DNA sensor; HSV-1; IκBα; NF-κB; UL36
Free PMC Article
6.
Carrà G, Panuzzo C, Crivellaro S, Morena D, Taulli R, Guerrasio A, Saglio G, Morotti A.
Oncol Lett. 2016 Nov;12(5):3123-3126. Epub 2016 Sep 1.
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is driven by the p190 breakpoint cluster region (BCR)-ABL isoform. Although effectively targeted by BCR-ABL tyrosine kinase inhibitors (TKIs), ALL is associated with a less effective response to TKIs compared with chronic myeloid leukemia. Therefore, the identification of additional genes required for ALL maintenance may provide possible therapeutic targets to aid the eradication of this cancer. The present study demonstrated that p190 BCR-ABL is able to interact with the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which in turn affects p53 protein stability. Notably, the inhibition of HAUSP with small molecule inhibitors promoted the upregulation of p53 protein levels. These results suggest that HAUSP inhibitors may harbor clinically relevant implications in the treatment of Ph+ ALL. KEYWORDS:
BCR-ABL; acute lymphoblastic leukemia; herpesvirus-associated ubiquitin-specific protease; herpesvirus-associated ubiquitin-specific protease inhibitors; p190; p53 DOI: 10.3892/ol.2016.5073
Free PMC Article
7.
Campbell EM, Weingart J, Sette P, Opp S, Sastri J, O'Connor SK, Talley S, Diaz-Griffero F, Hirsch V, Bouamr F.
J Virol. 2015 Dec 16;90(4):1849-57. doi: 10.1128/JVI.01948-15. Print 2016 Feb 15.
8.
Bhattacharya S, Ghosh MK.
FEBS J. 2014 Jul;281(13):3061-78. doi: 10.1111/febs.12843. Epub 2014 Jun 10.
Tumor suppressor retinoblastoma-associated protein (Rb) is an important cell cycle regulator, arresting cells in early G1. It is commonly inactivated in cancers and its level is maintained during the cell cycle. Rb is regulated by various post-translational modifications such as phosphorylation, acetylation, ubiquitination and so on. Several E3 ligases including murine double minute 2 (MDM2) promote the degradation of Rb. This study focuses on the role of HAUSP (herpes virus associated ubiquitin specific protease) on Rb. Here, we show that HAUSP colocalizes and interacts with Rb to stabilize it from proteasomal degradation by removing wild-type and K48-linked ubiquitin chains in human embryonic kidney 293 (HEK293) cells. HAUSP deubiquitinates Rb in vivo and in vitro, leading to an increased cell population in the G1 phase. Hence, HAUSP is a novel deubiquitinase for Rb. Immunohistochemistry, western blotting and cell-based assays show that HAUSP is overexpressed in glioma and contributes towards glioma progression. However, HAUSP activity on Rb is abrogated in glioma (cancer), where these two proteins show an inverse relationship. MDM2 (a known substrate of HAUSP) serves as a better target for HAUSP-mediated deubiquitination in cancer cells, facilitating degradation of Rb and oncogenic progression. This novel regulatory axis is proteasome mediated, p53 independent, and the level of MDM2 is critical. The shift in equilibrium by differential deubiquitination in regulation of Rb explains a subtle difference existing between normal and cancer cells. This leads to speculation about a new possibility for distinguishing cancer cells from normal cells at the molecular level, which may be investigated for therapeutic intervention in the future.
Rb; deubiquitination; glioma; herpes virus associated ubiquitin specific protease; murine double minute 2. DOI: 10.1111/febs.12843
Free PMC Article
9.
van Gent M, Braem SG, de Jong A, Delagic N, Peeters JG, Boer IG, Moynagh PN, Kremmer E, Wiertz EJ, Ovaa H, Griffin BD, Ressing ME.
PLoS Pathog. 2014 Feb 20;10(2):e1003960. doi: 10.1371/journal.ppat.1003960. eCollection 2014 Feb.

Abstract

Viral infection triggers an early host response through activation of pattern recognition receptors, including Toll-like receptors (TLR). TLR signaling cascades induce production of type I interferons and proinflammatory cytokines involved in establishing an anti-viral state as well as in orchestrating ensuing adaptive immunity. To allow infection, replication, and persistence, (herpes)viruses employ ingenious strategies to evade host immunity. The human gamma-herpesvirus Epstein-Barr virus (EBV) is a large, enveloped DNA virus persistently carried by more than 90% of adults worldwide. It is the causative agent of infectious mononucleosis and is associated with several malignant tumors. EBV activates TLRs, including TLR2, TLR3, and TLR9. Interestingly, both the expression of and signaling by TLRs is attenuated during productive EBV infection. Ubiquitination plays an important role in regulating TLR signaling and is controlled by ubiquitin ligases and deubiquitinases (DUBs). The EBV genome encodes three proteins reported to exert in vitro deubiquitinase activity. Using active site-directed probes, we show that one of these putative DUBs, the conserved herpesvirus large tegument protein BPLF1, acts as a functional DUB in EBV-producing B cells. The BPLF1 enzyme is expressed during the late phase of lytic EBV infection and is incorporated into viral particles. The N-terminal part of the large BPLF1 protein contains the catalytic site for DUB activity and suppresses TLR-mediated activation of NF-κB at, or downstream of, the TRAF6 signaling intermediate. A catalytically inactive mutant of this EBV protein did not reduce NF-κB activation, indicating that DUB activity is essential for attenuating TLR signal transduction. Our combined results show that EBV employs deubiquitination of signaling intermediates in the TLR cascade as a mechanism to counteract innate anti-viral immunity of infected hosts DOI: 10.1371/journal.ppat.1003960 [Indexed for MEDLINE]
10.
Wang S, Wang K, Li J, Zheng C.
J Virol. 2013 Nov;87(21):11851-60. doi: 10.1128/JVI.01211-13. Epub 2013 Aug 28.
Interferon (IFN)-mediated innate immune defense is a potent antiviral mechanism. Viruses evade innate immunity and limit secretion of beta interferon (IFN-β) to replicate and survive in the host. The largest tegument protein of herpes simplex virus 1 (HSV-1), UL36, contains a novel deubiquitinase (DUB) motif embedded in its N terminus, denoted UL36 ubiquitin-specific protease (UL36USP). In the present study, we demonstrate that HSV-1 UL36USP inhibits Sendai virus (SeV)-induced interferon regulatory factor 3 (IRF3) dimerization, promoter activation, and transcription of IFN-β. The DUB activity of UL36USP is essential to block IFN-β production. UL36USP also inhibited IFN-β promoter activity induced by overexpression of the N terminus of RIG-I (RIG-IN) and MAVS, but not TBK-1, IκB kinase ε (IKKε), and IRF3/5D. UL36USP was subsequently shown to deubiquitinate TRAF3 and prevent the recruitment of the downstream adaptor TBK1. The recombinant HSV-1 lacking UL36USP DUB activity was generated. Cells infected with the mutant virus produced more IFN-β than wild-type (WT) HSV-1-infected cells. These findings demonstrate HSV-1 UL36USP removes polyubiquitin chains on TRAF3 and counteracts the IFN-β pathway.Free PMC Article
11.
Bronner C.
Sci Signal. 2011 Jan 25;4(157):pe3. doi: 10.1126/scisignal.2001764.
Inheritance of DNA methylation patterns is a key mechanism involved in epigenetic cell memory transmission from mother cell to daughter cell. This occurs due to cooperation between the DNA methyltransferase DNMT1 and the ubiquitin ligase UHRF1 (ubiquitin-like, containing plant homeo domain and RING finger 1) in a macromolecular complex. Newly identified members of this complex are the acetyltransferase Tip60 (Tat-interactive protein) and the deubiquitinase HAUSP (herpes virus-associated ubiquitin specific protease), which exert tight regulation of DNMT1 abundance through a ubiquitylation-dependent process. It is important to determine how all of these actors communicate with each other and what signals coordinate their communication. In the case of DNMT1, the balance of UHRF1 and HAUSP activities might be influenced by the local environment, such as histone code, cell-cycle status, and local DNA methylation status.DOI: 10.1126/scisignal.2001764

13.
Kim ET, Oh SE, Lee YO, Gibson W, Ahn JH.
J Virol. 2009 Dec;83(23):12046-56. doi: 10.1128/JVI.00411-09. Epub 2009 Sep 16.
Our findings demonstrate that the HCMV UL48 DUB contains both a ubiquitin-specific carboxy-terminal hydrolase activity and an isopeptidase activity that favors ubiquitin Lys63 linkages and that these activities can influence virus replication in cultured cells.Free PMC Article

Ubikitinaasit, Deubikitinaasit, IFN , STAT ja virukset ( Dengue, ZIKA ja HCV )

https://www.ncbi.nlm.nih.gov/pubmed/?term=Deubiquitinases%2C+Dengue


 
1. Ensinnäkin miten  hepatiittivirus HCV, dengue ja Zikavirus  saavat ubikitinaationsa?  Niiden  NS2 proteiini saa K63 linkkiytyneen polyubikitiiniketjun E3-ligaasilla, jonka nimi on MARCH8.
Tämä modifikaatio avustaa virusta infektoimisessa  ja HCV virusta vielä virusvaipan hankkimisessa. K63- polyubikitiinimodifikaatio välittää  ESCRT-0 komponenttiin HRS  sitoutumista eli toimii pääsynä  solun   koneistoon, jolla virus  saa lopulta  itselleen   tehtyä  vaipparakennetta ja  pääsyä edelleen.
Viruksen NS joutuu kohtamaan solun sisällä E3 ubikitinaaseja,deubikitinaaseja ja ligaasin säätelijöitä, joista tulee jokoproviraalia tai antiviraalia vaikutusta. Isäntäkehon  E3 ligaasi MARCH8  RING finger-proteiini on todettu  avustavaksi  K63- polyubikitinaatiolla.
Tällaiseen  kohtaan vaikuttavalla deubikitinaasilla olisi sitten loogisesti ajatellen  antivirusvaikutusta ja tästä taas evolutionaalisesi ajatellen aikakausien  ollessa  äärettömän pitkiä virukset lienevät jo kehittäneen oman vDUB, joka kilpailee isäntäkehön sen DUB- entsyyminkanssa,joka  poistaa K63 polyubikitiinejä ja   avustaa  proteiinien joutumista silppuriin.  Tämä artikkeli paljastaa  siis vain  E3-ubikitiiniligaasityypin (MARCH8)  tässä yhteydessä.

Kumar S, Barouch-Bentov R, Xiao F, Schor S, Pu S, Biquand E, Lu A, Lindenbach BD, Jacob Y, Demeret C, Einav S.
Cell Rep. 2019 Feb 12;26(7):1800-1814.e5. doi: 10.1016/j.celrep.2019.01.075. Abstract
The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) binding and envelopment. Nevertheless, the ubiquitin signaling that governs NS2 ubiquitination remained unknown. Here, we map the NS2 interactome with the ubiquitin proteasome system (UPS) via mammalian cell-based screens. NS2 interacts with E3 ligases, deubiquitinases, and ligase regulators, some of which are candidate proviral or antiviral factors. MARCH8, a RING-finger E3 ligase, catalyzes K63-linked NS2 polyubiquitination in vitro and in HCV-infected cells. MARCH8 is required for infection with HCV, dengue, and Zika viruses and specifically mediates HCV envelopment. Our data reveal regulation of HCV envelopment via ubiquitin signaling and both a viral protein substrate and a ubiquitin K63-linkage of the understudied MARCH8, with potential implications for cell biology, virology, and host-targeted antiviral design.
ESCRT; HCV; MARCH8; assembly; envelopment; hepatitis C virus; intracellular membrane trafficking; proteomics; ubiquitination; virus-host interactions
Free Article
2.
Giraldo MI, Vargas-Cuartas O, Gallego-Gomez JC, Shi PY, Padilla-Sanabria L, Castaño-Osorio JC, Rajsbaum R.
Virus Res. 2018 Feb 15;246:1-11. doi: 10.1016/j.virusres.2017.12.013. Epub 2017 Dec 30. PMID: 29294313  Abstract Dengue virus (DENV) is a member of the Flaviviridae family, which is transmitted to mammalian species through arthropods, and causes dengue fever or severe dengue fever in humans. The DENV genome encodes for multiple nonstructural (NS) proteins including NS1. NS1 plays an essential role in replication by interacting with other viral proteins including NS4B, however how these interactions are regulated during virus infection is not known. By using bioinformatics, mass spectrometry analysis, and co-immunoprecipitation assays, here we show that DENV-NS1 is ubiquitinated on multiples lysine residues during DENV infection, including K189, a lysine residue previously shown to be important for efficient DENV replication. Data from in vitro and cell culture experiments indicate that dengue NS1 undergoes modification with K48-linked polyubiquitin chains, which usually target proteins to the proteasome for degradation. Furthermore, ubiquitinated NS1 was detected in lysates as well as in supernatants of human and mosquito infected cells. Ubiquitin deconjugation of NS1 using the deubiquitinase OTU resulted in increased interaction with the viral protein NS4B suggesting that ubiquitinated NS1 has reduced affinity for NS4B. In support of these data, a K189R mutation on NS1, which abrogates ubiquitination on amino acid residue 189 of NS1, also increased NS1-NS4B interactions. Our work describes a new mechanism of regulation of NS1-NS4B interactions and suggests that ubiquitination of NS1 may affect DENV replication.
3.
Yeh HM, Yu CY, Yang HC, Ko SH, Liao CL, Lin YL.
J Immunol. 2013 Sep 15;191(6):3328-36. doi: 10.4049/jimmunol.1300225. Epub 2013 Aug 12. Abstract. The IFN immune system com prises type I, II, and III IFNs, signals through the JAK-STAT pathway, and plays central roles in host defense against viral infection. Posttranslational modifications (PTM)  such as ubiquitination regulate diverse molecules in the IFN pathway. To search for the deubiquitinating enzymes (DUBs) involved in the antiviral activity of IFN, we used RNA interference screening to identify a human DUB, ubiquitin-specific protease (USP) 13, whose expression modulates the antiviral activity of IFN-α against dengue virus serotype 2 (DEN-2). The signaling events and anti-DEN-2 activities of IFN-α and IFN-γ were reduced in cells with USP13 knockdown but enhanced with USP13 overexpression. USP13 may regulate STAT1 protein because the protein level and stability of STAT1 were increased with USP13 overexpression. Furthermore, STAT1 ubiquitination was reduced in cells with USP13 overexpression and increased with USP13 knockdown regardless of with or without IFN-α treatment. Thus, USP13 positively regulates type I and type II IFN signaling by deubiquitinating and stabilizing STAT1 protein. Overall, to our knowledge, USP13 is the first DUB identified to modulate STAT1 and play a role in the antiviral activity of IFN against DEN-2 replication.
4.
Nag DK, Finley D.
Virus Res. 2012 Apr;165(1):103-6. doi: 10.1016/j.virusres.2012.01.009. Epub 2012 Jan 26.
PMID:
22306365

Deubikitinaasit virusinfektiossa, hDUB ja vDUB

https://www.ncbi.nlm.nih.gov/pubmed/28885059

2018 May;44(3):304-317. doi: 10.1080/1040841X.2017.1368999. Epub 2017 Sep 8.
Viral deubiquitinases: role in evasion of anti-viral innate immunity.
Kumari P1, Kumar H1. Abstract
Host anti-viral innate-immune signalling pathways are regulated by a variety of post-translation modifications including ubiquitination, which is critical to regulate various signalling pathways for synthesis of anti-viral molecules. A homeostasis of host immune responses, induced due to viral infection and further ubiquitination, is maintained by the action of deubiquitinases (DUB). Infecting viruses utilize the process of deubiquitination for tricking host immune system wherein viral DUBs compete with host DUBs for inhibition of innate-immune anti-viral signalling pathways, which instead of maintaining an immune homeostasis bring about virus-mediated pathogenesis. This suggests that viruses co-evolve with their hosts to acquire similar machinery for tricking immune surveillance and establishing infection. KEYWORDS:
Viruses; anti-viral innate-immune signalling; host deubiquitinases; pattern recognition receptors; type I interferons; viral deubiquitinases PMID: 28885059 DOI: 10.1080/1040841X.2017.1368999

söndag 19 maj 2019

MItä solun luonnollisessa puolustuksessa tapahtuu virusinfektiossa?



2019 Apr 17;10:836. doi: 10.3389/fimmu.2019.00836. eCollection 2019.

Analysis of Global Transcriptome Change in Mouse Embryonic Fibroblasts After dsDNA and dsRNA Viral Mimic Stimulation.

Abstract

The activation of innate immunity by viral nucleic acids present in the cytoplasm plays an essential role in controlling viral infection in both immune and non-immune cells. The dsDNA and dsRNA viral mimics can stimulate the cytosolic nucleic acids sensors and activate the antiviral innate immunity.
 In this study, taking advantage of dsDNA and dsRNA viral mimics, we investigated the global transcriptome changes after the antiviral immunity activation in mouse embryonic fibroblasts.

Results from our data identified a positive feedback up-regulation of sensors (e.g., Tlr2, Tlr3, Ddx58, cGAS), transducers (e.g., Traf2, Tbk1) and transcription factors (e.g., Irf7, Jun, Stat1, Stat2) in multiple pathways involved in detecting viral or microbial infections upon viral mimic stimulation.

A group of genes involved in DNA damage response and DNA repair such as Parp9, Dtx3l, Rad52 were also up-regulated, implying the involvement of these genes in antiviral immunity.

Molecular function analysis further showed that groups of helicase genes (e.g., Dhx58, Helz2), nuclease genes (e.g., Dnase1l3, Rsph10b), methyltransferase genes (e.g., histone methyltransferase Prdm9, Setdb2; RNA methyltransferase Mettl3, Mttl14), and protein ubiquitin-ligase genes (e.g., Trim genes and Rnf genes) were up-regulated upon antiviral immunity activation.

 In contrast, viral mimic stimulation down-regulated genes involved in a broad range of general biological processes (e.g., cell division, metabolism), cellular components (e.g., mitochondria and ribosome), and molecular functions (e.g., cell-cell adhesion, microtubule binding).

 In summary, our study provides valuable information about the global transcriptome changes upon antiviral immunity activation.

 The identification of novel groups of genes up-regulated upon antiviral immunity activation serves as useful resource for mining new antiviral sensors and effectors.

KEYWORDS:

genome-wide analysis; innate immunity; mouse embryonic fibroblasts; transcriptional profiling; viral mimic stimulation
PMID:
31057555
PMCID:
PMC6478819
DOI:
10.3389/fimmu.2019.00836

fredag 17 maj 2019

Sisäisestä genomisesta antiviruspuolustuksesta esimerkkiä

 Histoni H3.3
Geeni HIRA (22q11.21) , histone cell cycle regulator
DGCR1, HIRA, TUP1, TUPLE1 (22q11.21)
https://academic.oup.com/nar/article/45/20/11673/4128795

Histone chaperone HIRA deposits histone H3.3 onto foreign viral DNA and contributes to anti-viral intrinsic immunity

Nucleic Acids Research, Volume 45, Issue 20, 16 November 2017, Pages 11673–11683, https://doi.org/10.1093/nar/gkx771
Published:
13 September 2017
Article history

Abstract



The HIRA histone chaperone complex deposits histone H3.3 into nucleosomes in a DNA replication- and sequence-independent manner. As herpesvirus genomes enter the nucleus as naked DNA, we asked whether the HIRA chaperone complex affects herpesvirus infection. After infection of primary cells with HSV or CMV, or transient transfection with naked plasmid DNA, HIRA re-localizes to PML bodies, sites of cellular anti-viral activity. HIRA co-localizes with viral genomes, binds to incoming viral and plasmid DNAs and deposits histone H3.3 onto these. Anti-viral interferons (IFN) specifically induce HIRA/PML co-localization at PML nuclear bodies and HIRA recruitment to IFN target genes, although HIRA is not required for IFN-inducible expression of these genes. HIRA is, however, required for suppression of viral gene expression, virus replication and lytic infection and restricts murine CMV replication in vivo. We propose that the HIRA chaperone complex represses incoming naked viral DNAs through chromatinization as part of intrinsic cellular immunity.


tisdag 7 maj 2019

Norjalainen nuori nainen menehtyi rabiekseen

https://www.aftonbladet.se/nyheter/a/WboE5j/rabiessmittad-ung-kvinna-har-dott

NYHETER
Hon smittades med rabies efter att ha blivit biten av en hund i Asien.
Nu har kvinnan i 20-årsåldern dött på sjukhus i Norge.

Väl hemma har personen blivit sämre och sämre och sökte vård på sjukhuset i Førde, på norska västkusten.
I torsdags förra veckan las kvinnan in på centralsjukhuset i Førde på norska västkusten.
Hon var förvirrad och när det framkom att hon blivit biten av en hund under en semesterresa i Sydostasien för två månader sedan misstänkte sjukhuset i Førde att hon smittats av rabies.
Prover skickades till Folkhälsomyndigheten i Sverige som i lördags bekräftade misstankarna:
Den unga kvinnan hade rabies.
– Patienten var inlagd på vår intensivavdelning och dog lugnt och stilla tidigt på måndagskvällen, omgiven av sin familj, säger Trine Hunskår Vingsnes, chef vid sjukvården i Fønde, i ett pressmeddelande.
Det är första gången sedan 1815 som en norsk medborgare på fastlandet har drabbats av rabies.
Kvinnan bodde i Sogn og Fjordarne på norska västkusten, enligt VG.
De andra som var med på samma resa kom också i kontakt med samma hund, som bet turisten, men de bor på andra platser i Norge.
Smittskyddsansvariga i deras respektive hemkommuner är larmade och har vidtagit nödvändiga åtgärder.
Rabies smittar via saliv, vanligtvis från hundar, men någon dokumentation om att det har smittat mellan människor finns inte.
Sjukdomen förekommer mest i Asien, Afrika och Nord-, Mellan- och Sydamerika.
Rabies är en dödlig sjukdom om du inte får vård tidigt.
Symtomen är domningar och smärta kring bettet, ångest,  hallucinationer, huvudvärk, förvirring och kramper – och har sjukdomen gått så långt är den alltid dödlig.