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  1. Article: The Role of Atypical Ubiquitin Chains in the Regulation of the Antiviral Innate Immune Response.

    van Huizen, Mariska / Kikkert, Marjolein

    Frontiers in cell and developmental biology

    2020  Volume 7, Page(s) 392

    Abstract: It is well established that polyubiquitin chains, in particular those linked through K48 and K63, play a key role in the regulation of the antiviral innate immune response. However, the role of the atypical chains linked via any of the other lysine ... ...

    Abstract It is well established that polyubiquitin chains, in particular those linked through K48 and K63, play a key role in the regulation of the antiviral innate immune response. However, the role of the atypical chains linked via any of the other lysine residues (K6, K11, K27, K29, and K33) and the M1-linked linear chains have not been investigated very well yet in this context. This is partially due to a lack of tools to study these linkages in their biological context. Interestingly though, recent findings underscore the importance of the atypical chains in the regulation of the antiviral immune response. This review will highlight the most important advances in the study of the role of atypical ubiquitin chains, particularly in the regulation of intracellular antiviral innate immune signaling pathways. We will also discuss the development of new tools and how these can increase our knowledge of the role of atypical ubiquitin chains.
    Language English
    Publishing date 2020-01-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2019.00392
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The Main Protease of Middle East Respiratory Syndrome Coronavirus Induces Cleavage of Mitochondrial Antiviral Signaling Protein to Antagonize the Innate Immune Response.

    van Huizen, Mariska / Vendrell, Xavier M / de Gruyter, Heidi L M / Boomaars-van der Zanden, A Linda / van der Meer, Yvonne / Snijder, Eric J / Kikkert, Marjolein / Myeni, Sebenzile K

    Viruses

    2024  Volume 16, Issue 2

    Abstract: Mitochondrial antiviral signaling protein (MAVS) is a crucial signaling adaptor in the sensing of positive-sense RNA viruses and the subsequent induction of the innate immune response. Coronaviruses have evolved multiple mechanisms to evade this response, ...

    Abstract Mitochondrial antiviral signaling protein (MAVS) is a crucial signaling adaptor in the sensing of positive-sense RNA viruses and the subsequent induction of the innate immune response. Coronaviruses have evolved multiple mechanisms to evade this response, amongst others, through their main protease (M
    MeSH term(s) Middle East Respiratory Syndrome Coronavirus ; Immunity, Innate ; Interferon-beta/metabolism ; Peptide Hydrolases ; Antiviral Agents
    Chemical Substances Interferon-beta (77238-31-4) ; Peptide Hydrolases (EC 3.4.-) ; Antiviral Agents
    Language English
    Publishing date 2024-02-05
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v16020256
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Deubiquitinating activity of SARS-CoV-2 papain-like protease does not influence virus replication or innate immune responses in vivo.

    van Huizen, Mariska / Bloeme-Ter Horst, Jonna R / de Gruyter, Heidi L M / Geurink, Paul P / van der Heden van Noort, Gerbrand J / Knaap, Robert C M / Nelemans, Tessa / Ogando, Natacha S / Leijs, Anouk A / Urakova, Nadya / Mark, Brian L / Snijder, Eric J / Myeni, Sebenzile K / Kikkert, Marjolein

    PLoS pathogens

    2024  Volume 20, Issue 3, Page(s) e1012100

    Abstract: The coronavirus papain-like protease (PLpro) is crucial for viral replicase polyprotein processing. Additionally, PLpro can subvert host defense mechanisms by its deubiquitinating (DUB) and deISGylating activities. To elucidate the role of these ... ...

    Abstract The coronavirus papain-like protease (PLpro) is crucial for viral replicase polyprotein processing. Additionally, PLpro can subvert host defense mechanisms by its deubiquitinating (DUB) and deISGylating activities. To elucidate the role of these activities during SARS-CoV-2 infection, we introduced mutations that disrupt binding of PLpro to ubiquitin or ISG15. We identified several mutations that strongly reduced DUB activity of PLpro, without affecting viral polyprotein processing. In contrast, mutations that abrogated deISGylating activity also hampered viral polyprotein processing and when introduced into the virus these mutants were not viable. SARS-CoV-2 mutants exhibiting reduced DUB activity elicited a stronger interferon response in human lung cells. In a mouse model of severe disease, disruption of PLpro DUB activity did not affect lethality, virus replication, or innate immune responses in the lungs. This suggests that the DUB activity of SARS-CoV-2 PLpro is dispensable for virus replication and does not affect innate immune responses in vivo. Interestingly, the DUB mutant of SARS-CoV replicated to slightly lower titers in mice and elicited a diminished immune response early in infection, although lethality was unaffected. We previously showed that a MERS-CoV mutant deficient in DUB and deISGylating activity was strongly attenuated in mice. Here, we demonstrate that the role of PLpro DUB activity during infection can vary considerably between highly pathogenic coronaviruses. Therefore, careful considerations should be taken when developing pan-coronavirus antiviral strategies targeting PLpro.
    MeSH term(s) Humans ; Animals ; Mice ; Coronavirus Papain-Like Proteases/genetics ; COVID-19 ; SARS-CoV-2/metabolism ; Immunity, Innate ; Papain/genetics ; Papain/metabolism ; Peptide Hydrolases/metabolism ; Virus Replication ; Polyproteins
    Chemical Substances papain-like protease, SARS-CoV-2 (EC 3.4.22.2) ; Coronavirus Papain-Like Proteases (EC 3.4.22.2) ; Papain (EC 3.4.22.2) ; Peptide Hydrolases (EC 3.4.-) ; Polyproteins
    Language English
    Publishing date 2024-03-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1012100
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site.

    van Vliet, Vera J E / Huynh, Nhan / Palà, Judith / Patel, Ankoor / Singer, Alex / Slater, Cole / Chung, Jacky / van Huizen, Mariska / Teyra, Joan / Miersch, Shane / Luu, Gia-Khanh / Ye, Wei / Sharma, Nitin / Ganaie, Safder S / Russell, Raquel / Chen, Chao / Maynard, Mindy / Amarasinghe, Gaya K / Mark, Brian L /
    Kikkert, Marjolein / Sidhu, Sachdev S

    PLoS pathogens

    2022  Volume 18, Issue 12, Page(s) e1011065

    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses-including SARS- ... ...

    Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses-including SARS-CoV, MERS-CoV, and SARS-CoV-2-is the papain-like protease (PLpro). PLpro cleaves part of the viral replicase polyproteins into non-structural protein subunits, which are essential to the viral replication cycle. Additionally, PLpro can cleave both ubiquitin and the ubiquitin-like protein ISG15 from host cell substrates as a mechanism to evade innate immune responses during infection. These roles make PLpro an attractive antiviral drug target. Here we demonstrate that ubiquitin variants (UbVs) can be selected from a phage-displayed library and used to specifically and potently block SARS-CoV-2 PLpro activity. A crystal structure of SARS-CoV-2 PLpro in complex with a representative UbV reveals a dimeric UbV bound to PLpro at a site distal to the catalytic site. Yet, the UbV inhibits the essential cleavage activities of the protease in vitro and in cells, and it reduces viral replication in cell culture by almost five orders of magnitude.
    MeSH term(s) Humans ; Ubiquitin/metabolism ; Peptide Hydrolases/metabolism ; SARS-CoV-2/metabolism ; Catalytic Domain ; COVID-19 ; Papain/chemistry ; Papain/metabolism ; Virus Replication
    Chemical Substances Ubiquitin ; Peptide Hydrolases (EC 3.4.-) ; Papain (EC 3.4.22.2)
    Language English
    Publishing date 2022-12-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1011065
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The helminth glycoprotein omega-1 improves metabolic homeostasis in obese mice through type 2 immunity-independent inhibition of food intake.

    van der Zande, Hendrik J P / Gonzalez, Michael A / de Ruiter, Karin / Wilbers, Ruud H P / García-Tardón, Noemí / van Huizen, Mariska / van Noort, Kim / Pelgrom, Leonard R / Lambooij, Joost M / Zawistowska-Deniziak, Anna / Otto, Frank / Ozir-Fazalalikhan, Arifa / van Willigen, Danny / Welling, Mick / Poles, Jordan / van Leeuwen, Fijs / Hokke, Cornelis H / Schots, Arjen / Yazdanbakhsh, Maria /
    Loke, P'ng / Guigas, Bruno

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2021  Volume 35, Issue 2, Page(s) e21331

    Abstract: Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta-inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its ... ...

    Abstract Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta-inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet, a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega-1 (ω1), one of the major S mansoni immunomodulatory glycoproteins, on metabolic homeostasis. We show that treatment of obese mice with plant-produced recombinant ω1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass, and improved systemic insulin sensitivity and glucose tolerance in a time- and dose-dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils, and alternatively activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of ω1 were still observed in obese STAT6-deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that ω1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole-body energy expenditure, an effect also occurring in leptin receptor-deficient obese and hyperphagic db/db mice. Altogether, we demonstrate that while the helminth glycoprotein ω1 can induce type 2 immunity, it improves whole-body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6-independent mechanism.
    MeSH term(s) Adipose Tissue/drug effects ; Adipose Tissue/metabolism ; Animals ; Cells, Cultured ; Eating ; Endoribonucleases/pharmacology ; Endoribonucleases/therapeutic use ; Glycoproteins/pharmacology ; Glycoproteins/therapeutic use ; Helminth Proteins/pharmacology ; Helminth Proteins/therapeutic use ; Locomotion ; Macrophages/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/drug therapy ; Recombinant Proteins/pharmacology ; Recombinant Proteins/therapeutic use ; Schistosoma mansoni/enzymology ; T-Lymphocytes, Helper-Inducer/drug effects ; Thermogenesis ; Nicotiana/genetics ; Nicotiana/metabolism
    Chemical Substances Glycoproteins ; Helminth Proteins ; Recombinant Proteins ; Endoribonucleases (EC 3.1.-) ; ribonuclease T(2) (EC 3.1.27.1)
    Language English
    Publishing date 2021-01-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202001973R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2266: Show issues Location:
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    Zs.MO 296: Show issues

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  6. Article ; Online: The helminth glycoprotein omega‐1 improves metabolic homeostasis in obese mice through type 2 immunity‐independent inhibition of food intake

    van der Zande, Hendrik J.P. / Gonzalez, Michael A. / Ruiter, Karin / Wilbers, Ruud H.P. / García‐Tardón, Noemí / van Huizen, Mariska / van Noort, Kim / Pelgrom, Leonard R. / Lambooij, Joost M. / Zawistowska‐Deniziak, Anna / Otto, Frank / Ozir‐Fazalalikhan, Arifa / van Willigen, Danny / Welling, Mick / Poles, Jordan / Leeuwen, Fijs / Hokke, Cornelis H. / Schots, Arjen / Yazdanbakhsh, Maria /
    Loke, P. / Guigas, Bruno

    FASEB Journal

    2021  Volume 35, Issue 2

    Abstract: Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta‐inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its ... ...

    Abstract Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta‐inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet, a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega‐1 (ω1), one of the major S mansoni immunomodulatory glycoproteins, on metabolic homeostasis. We show that treatment of obese mice with plant‐produced recombinant ω1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass, and improved systemic insulin sensitivity and glucose tolerance in a time‐ and dose‐dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils, and alternatively activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of ω1 were still observed in obese STAT6‐deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that ω1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole‐body energy expenditure, an effect also occurring in leptin receptor‐deficient obese and hyperphagic db/db mice. Altogether, we demonstrate that while the helminth glycoprotein ω1 can induce type 2 immunity, it improves whole‐body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6‐independent mechanism.
    Keywords helminths ; immunometabolism ; insulin sensitivity ; macrophages ; type 2 immunity
    Subject code 570
    Language English
    Publishing country nl
    Document type Article ; Online
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2266: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 296: Show issues

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