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lördag 14 december 2019

GUPEA : Musiineja käsitteleviä väitöskirjoja: LANG T (2007) Musiinievoluutiosta

2007 LANG Tiange
https://gupea.ub.gu.se/handle/2077/7502

Title: Evolution of Transmembrane and Gel-forming Mucins Studied with Bioinformatic Methods
Authors: Tiange, Lang
E-mail: lang_tiange@hotmail.com
Issue Date: 13-Nov-2007
University: Göteborg University. Sahlgrenska Academy
Institution: Inst of Biomedicine. Dept of Medical Biochemistry and Cell Biology
Parts of work: Lang T., Alexandersson M., Hansson G. C. and Samuelsson T. (2004) Bioinformatic identification of polymerizing and transmembrane mucins in the puffer fish Fugu rubripes. Glycobiology 14:521-527.
VIEW ARTICLE


Lang T., Hansson G. C. and Samuelsson T. (2006) An inventory of mucin genes in the chicken genome shows that the mucin domain of Muc13 is encoded by multiple exons and that ovomucin is part of a locus of related gel-forming mucins. BMC Genomics. 7:197-206.
VIEW ARTICLE


Lang, T., Hansson, G. C. and Samuelsson T. (2007) Gel-forming mucins appeared early in metazoan evolution. Proc Natl Acad Sci U S A. 104(41):16209-16214.
VIEW ARTICLE
All mucosal membranes of the body are covered by mucus, largely made up of the family of large glycoproteins called mucins. These are instrumental for the protection of the underlying epithelia and involved in the pathogenesis of many diseases in the lungs and the intestine. Several mucins are also involved in the progression of cancer and can often be linked to bad prognosis. The mucins are classified as membrane-bound or secreted. In human there are eight membrane-bound (MUC1, MUC3, MUC4, MUC12, MUC13, MUC15, MUC16 and MUC17) and five secreted and gel-forming mucins (MUC2, MUC5B, MUC5AC, MUC6, and MUC19). Mucins are characterized by domains rich in proline, serine and threonine that are heavily glycosylated (PTS domains) and typically have either von Willebrand D (VWD) or SEA domains. To aid in understanding this family of proteins we have taken a bioinformatics approach to mine protein and genomic sequence databases for mucins. We have combined different methods to predict mucin proteins. We developed PTSpred, a method to predict PTS domains characteristic of mucins. We also made use of prediction of signal sequences, transmembrane regions, profile based searches and methods to predict genomic regions encoding specific protein domains. We have examined several animals with respect to mucins and other proteins that contain the VWD and SEA domains and have identified numerous novel mucin homologues and mucin-related proteins. We first made an comprehsnsive inventory of human, mouse and rat mucins including the human chromosome 7q22 region which encodes MUC3, MUC12, and MUC17. During the analysis of the chicken genome we found that the homologues of human chromosome 11p15 gel-forming mucin group (MUC6, MUC2, MUC5AC and MUC5B) are found with the same order as in human, and Muc13 is encoded by a gene where the PTS domain is divided among several exons, where each exon encodes a repeated unit in the protein. The mucins in Xenopus tropicalis are unusual in many respects. The number of gel-forming mucins has been markedly expanded, and the Muc2 homologues contain an unusual PTS domain rich in cysteines. In addition, Xenopus tropicalis has a novel family of mucin-like proteins with alternating PTS and SEA domains, a type of protein also identified in the fishes. The evolution of the MUC4 mucin seems to have occurred by recruitment of a PTS domain to NIDO, AMOP and VWD domains from a sushi-domain containing family of proteins present in lower animals. Xenopus tropicalis is the most deeply branching animal where a protein similar to the mammalian MUC4 was identified. In the gel-forming mucins, a VWD domain typically occurs together with a TIL domain and a domain we have named VWE. We also demonstrated that the gel-forming mucins, von Willebrand factor (VWF), otogelin and insect hemolectin are evolutionary related. Proteins related to these are found in a range of animals, including a mucin in the deeply branching metazoan Nematostella vectensis (sea anemone). This demonstrates an early origin of this group of mucins. In contrast, all the transmembrane mucins do not seem to have evolved until the appearance of the vertebrate lineage. ISBN: 978-91-628-7320-2 URI: http://hdl.handle.net/2077/7502 Appears in Collections: Doctoral Theses from Sahlgrenska Ac

tisdag 3 september 2019

WHO raportti lintuinfluenssatilanteesta 2019

https://www.who.int/influenza/human_animal_interface/Influenza_Summary_IRA_HA_interface_24_06_2019.pdf
1
 Influenza at the human-animal interface
 Summary and assessment, 11 May to 24 June 2019

 New infections1: 
Since the previous update on 10 May 2019, one new human infection with an influenza A(H1N1) variant virus was reported. 

Risk assessment: 
The overall public health risk from currently known influenza viruses at the human-animal interface (HA)  has not changed, and the likelihood of sustained human-to-human transmission of these viruses remains low.
 Further human infections with viruses of animal origin are expected. 

 IHR compliance
 All human infections caused by a new influenza subtype are required to be reported under the International Health Regulations (IHR, 2005).2 
This includes any influenza A virus that has demonstrated the capacity to infect a human and its haemagglutinin gene (or protein) is not a mutated form of those, i.e. A(H1)or A(H3), circulating widely in the human population. Information from these notifications is critical to inform risk assessments for influenza at the human-animal interface.


 Avian Influenza Viruses

Current situation:

 Avian influenza A(H5) viruses 
Since the last update on 10 May 2019, no new laboratory-confirmed human cases of influenza A(H5) virus infections were reported to WHO. According to reports received by the World Organisation for Animal Health (OIE), various influenza A(H5) subtypes continue to be detected in birds in Africa, Europe and Asia. Overall, the risk assessment has not changed.

 Avian influenza A(H7N9) viruses 
Since the last update on 10 May2019, no new laboratory-confirmed human cases of influenza A(H7N9) virus infections were reported to WHO. There have been no publicly available reports from animal health authorities in China of influenza A(H7N9) virus detections in animals in recent months.3
 Overall, the risk assessment has not changed

(Swine Influenza Viruses 
 Current situation...)

  Links:
 WHO Human-Animal Interface web page
 http://www.who.int/influenza/human_animal_interface/en/ 
WHO Protocol to investigate non-seasonal influenza and other emerging acute respiratory diseases
 http://www.who.int/influenza/resources/publications/outbreak_investigation_protocol/en/ 
Cumulative Number of Confirmed Human Cases of Avian Influenza A(H5N1) Reported to WHO
 http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/ 
Avian Influenza A(H7N9) Information
 http://www.who.int/influenza/human_animal_interface/influenza_h7n9/en/
 WHO Avian Influenza Food Safety Issues
 http://www.who.int/foodsafety/areas_work/zoonose/avian/en/
 World Organisation of Animal Health (OIE) web page: Web portal on Avian Influenza 
 http://www.oie.int/animal-health-in-the-world/web-portal-on-avian-influenza/
 Food and Agriculture Organization of the UN (FAO) webpage: Avian Influenza http://www.fao.org/avianflu/en/index.html 
OFFLU

 Tilanne globaalitasolla  kesällä 2019. 

Kysymyksiä ja vastauksia H5N1 lintuviruksesta (WHO)

https://www.who.int/influenza/human_animal_interface/avian_influenza/h5n1_research/faqs/en/
Kysymyksiä suomennettu 3.9. 2019

Q2: How does H5N1 influenza spread to people?

MitenH5N1 influenssa leviää ihmiseen?

Almost all cases of H5N1 infection in people have been associated with close contact with infected live or dead birds, or H5N1-contaminated environments. The virus does not infect humans easily, and spread from person to person appears to be unusual. There is no evidence that the disease can be spread to people through properly prepared and thoroughly cooked food.

Melkein joka tapaus, jossa ihminen on infektoitunut H5N1- viruksella, liittyy lähikontaktiin infektoituneitten elävien tai kuolleitten lintujen kanssa tai H5N1- viruksella kontaminoituun  ympäristöön. Tämä virus ei infektoi helposti ihmistä ja leviäminen henkilöstä toiseen näyttää olevan epätavallista. Ei ole näyttöä siitä, että tauti voisi levitä kunnollisesti valmistetun ja läpikotaisin keitetyn  ruoan välityksellä.

Q3: Why is there so much concern about H5N1 influenza? 

Minkä takia  niin paljon puhutaan juuri tästä H5N1-influenssasta? 

H5N1 infection in humans can cause severe disease and has a high mortality rate. If the H5N1 virus were to change and become easily transmissible from person to person while retaining its capacity to cause severe disease, the consequences for public health could be very serious.

Ihmisissä tämä H5N1- infektio voi aiheuttaa vakavan taudin ja silloin kuolleisuus on korkea.   Seuraamukset väestön terveystilassa voisivat olla hyvin vakavia, jos H5N1-virus muuntuisi siten, että se tulisi helposti  tarttuvaksi ihmisestä toiseen . mutta  olisi kuitenkin tautia aiheuttavalta kyvyltään yhtä hankala. 

Q4: Why might the H5N1 influenza virus change?

Minkätakia H5N1-virus saattaisi muuttua?

Influenza viruses constantly undergo genetic changes. It would be a cause for concern, should the H5N1 virus become more easily transmissible among humans.

Influenssaviruksissa tapahtuu jatkuvaa geneettistä muuntumista. Olisi  syytä huolestua, jos H5N1-virus tulisi helpommin  tarttuvaksi ihmisten keskuudessa.

Q5: What are the symptoms of H5N1 avian influenza in humans?

Minkälaisia oireita H5N1-lintuinfluenssa ihmisissä tuottaa?

The symptoms of H5N1 infection may include fever (often high fever, > 38°C) and malaise, cough, sore throat, and muscle aches. Other early symptoms may include abdominal pain, chest pain and diarrhoea. The infection may progress quickly to severe respiratory illness (for example, difficulty breathing or shortness of breath, pneumonia, Acute Respiratory Distress Syndrome) and neurologic changes (altered mental status or seizures).

 H5N1-infektion oireisiin   saattaa kuulua kuumetta, (joka on usein korkea , yli38 celsiusastetta), sairaudentunnetta, yskää, kipeää kurkkua ja lihaskipuja. Muihin varhaisiin oireisiin kuuluu vatsakipua, rintakipua ja ripulia. Infektio etenee nopeasti vaikeaksi hengitysteiden taudiksi ( esimerkiksi tulee  vaikeaksi hengittää, hengitys on  pinnallista, ilmenee keuhkokuumetta, akuuttia respiratorista oireyhtymää ARDS) ja  kehittyy neurologisia muutoksia ( henkinen tila muuttuu tai tulee kohtauksia).

Q6: Is it safe to eat chicken, poultry products and other wild game birds?

Onko turvallista syödä kanapoikaa, siipikarjatuotteita ja muuta linturiistaa?

Yes, it is safe to eat properly prepared and cooked poultry and game birds. The virus is sensitive to heat. Normal temperatures used for cooking (so that food reaches 70°C in all parts) will kill the virus. As a standard precaution, WHO recommends that poultry, poultry products and wild game birds should always be prepared following good hygienic practices, and that poultry meat should be properly cooked.
To date, a large number of human infections with the H5N1 virus have been linked to the home slaughter and subsequent handling of diseased or dead birds prior to cooking. These practices represent the highest risk of human infection and are the most important to avoid.

Kyllä vain: on turvallista syödä  asianmukaisesti valmistettua ja keitettyä siipikarjaa ja riistalintua. Virus on  herkkä kuumuudelle. Normaalit keittämiseen käytetyt lämpötilat ( kun joka kohta  linnunlihassa tulee 70 C asteen kuumuuteen)   tappavat viruksen.  Standardivarotoimenpiteeksi WHO suosittelee, että  siipikarja, siipikarjan tuotteet ja villiriistalinnut pitäisi aina esivalmistaa noudattaen hyvää hygienistä käytäntöä ja siipikarjan liha pitäisi keittää  asianmukaisesti.
Näihin asti on suuri määrä ihmisten H5N1-infektioista assosioitunut kodeissa tehtyyn teurastamiseen ja sen jälkeiseen tautia kantavien tai kuolleiden lintujen käsittelemiseen ennen ruoan valmistusta (keittämistä). Tärkeintä olisi välttää  tällaiset käytäntöjä, jotka   asettavat  ihmisen  suurimpaan infektoitumisen  riskiin .

Q7: How is H5N1 avian influenza in humans treated? 

Miten hoidetaan ihmisten H5N1 lintuinfluenssaa?

In most cases, avian influenza in humans develops into a serious disease that should be treated promptly in the hospital and may require intensive care, where available. The antiviral medicine oseltamivir can reduce the severity of illness and prevent death, and should be used in all cases.

Useimmissa tapauksissa lintuinfluenssa kehkeytyy  ihmisissä  vakavaksi taudiksi, joka pitäisi heti paikalla  hoitaa sairaalassa ja  saatetaan tarvita tehohoitoa siellä, missä sitä on  saatavilla.   Antiviruslääke oseltamivir saattaa vähentää taudin vakavuutta ja estää kuolemaa ja sitä pitäisi jokaisessa tapauksessa käyttää.

Q8: Is a vaccine available to prevent human infection with H5N1avian influenza?

Onko saatavilla rokotetta, joka estää ihmisen infektoitumisen H5N1 lintuviruksesta?

Candidate vaccines to prevent H5N1 infection have been developed, but they are not ready for widespread use.

On kehitetty H5N1 infektiota estäviä rokotekandidaatteja, mutta niitä ei ole valmiina laaja-alaiseen käyttöön. 

Q9: Does seasonal influenza (seasonal flu) vaccination provide protection against H5N1 viruses?

Antaako kausi-influenssarokotus suojaa H5N1viruksia vastaan?

Seasonal influenza vaccination does not appear to protect against H5N1 infection.

Kausi-influenssarokotus ei näytä suojaavan H5N1 infektiolta. 

Q10: What is the WHO response to H5N1 influenza?

Miten  WHO vastaa H5N1  influenssan  haasteeseen? 

WHO is working with countries to help them detect and manage cases of H5N1 infection in humans when they occur.
WHO collaborates with global health partners and agencies, including the World Organisation for Animal Health (OIE), and the Food and Agriculture Organization of the United Nations (FAO), to control and prevent the spread of animal diseases.
WHO’s global laboratory system, the Global Influenza Surveillance and Response System (GISRS), identifies and monitors strains of circulating influenza viruses, and provides advice to countries on their risk to human health and available treatment or control measures.

WHO tekee työtä  eri maitten kanssa auttaen niitä havaitsemaan ja hoitamaan H5N1 infekltiotapauksia, kun  niitä ihmisissä ilmenee.  
WHO tekee yhteistyötä  globaalien  terveysalan kollegoiden (partnereiden)  ja  virastojen (OIE, FAO, YK)  kanssa kontrolloiden eläinperäisiä sairauksia ja  estäen niiden leviämisiä. 
WHO:n globaali laboratoriojärjestelmä (GISRS) tunnistaa ja monitoroi kiertäviä influenssaviruskantoja ja  antaa neuvoja  maille  koskien  niiden väestön terveydellisiä riskejä ja saatavilla olevia  hoito- ja kontrollikeinoja. 

 https://www.who.int/influenza/preparedness/en/

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.