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  1. Article ; Online: Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis

    Karlowitz, Rebekka / van Wijk, Sjoerd J. L.

    The FEBS Journal. 2023 Jan., v. 290, no. 1 p.37-54

    2023  

    Abstract: Lytic forms of programmed cell death, like necroptosis, are characterised by cell rupture and the release of cellular contents, often provoking inflammatory responses. In the recent years, necroptosis has been shown to play important roles in human ... ...

    Abstract Lytic forms of programmed cell death, like necroptosis, are characterised by cell rupture and the release of cellular contents, often provoking inflammatory responses. In the recent years, necroptosis has been shown to play important roles in human diseases like cancer, infections and ischaemia/reperfusion injury. Coordinated interactions between RIPK1, RIPK3 and MLKL lead to the formation of a dedicated death complex called the necrosome that triggers MLKL‐mediated membrane rupture and necroptotic cell death. Necroptotic cell death is tightly controlled by post‐translational modifications, among which especially phosphorylation has been characterised in great detail. Although selective ubiquitination is relatively well‐explored in the early initiation stages of necroptosis, the mechanisms and functional consequences of RIPK3 and MLKL ubiquitination for necrosome function and necroptosis are only starting to emerge. This review provides an overview on how site‐specific ubiquitination of RIPK3 and MLKL regulates, fine‐tunes and reverses the execution of necroptotic cell death.
    Keywords death ; humans ; ischemia ; necroptosis ; phosphorylation ; reperfusion injury ; ubiquitination
    Language English
    Dates of publication 2023-01
    Size p. 37-54.
    Publishing place John Wiley & Sons, Ltd
    Document type Article ; Online
    Note REVIEW
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.16255
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 2006/704: Show issues

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  2. Book ; Online ; Thesis: The role of USP22 in nucleic acid sensing pathways and interferon-induced necroptotic cell death

    Karlowitz, Rebekka [Verfasser] / Dötsch, Volker [Gutachter] / Wijk, Sjoerd van [Gutachter]

    2024  

    Author's details Rebekka Karlowitz ; Gutachter: Volker Dötsch, Sjoerd van Wijk
    Keywords Biowissenschaften, Biologie ; Life Science, Biology
    Subject code sg570
    Language English
    Publisher Universitätsbibliothek Johann Christian Senckenberg
    Publishing place Frankfurt am Main
    Document type Book ; Online ; Thesis
    Database Digital theses on the web

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  3. Article ; Online: The Smac mimetic BV6 cooperates with STING to induce necroptosis in apoptosis-resistant pancreatic carcinoma cells.

    Hannes, Sabine / Karlowitz, Rebekka / van Wijk, Sjoerd J L

    Cell death & disease

    2021  Volume 12, Issue 9, Page(s) 816

    Abstract: Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we ... ...

    Abstract Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2'3'-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2'3'-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2'3'-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2'3'-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2'3'-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.
    MeSH term(s) Amino Acid Chloromethyl Ketones ; Apoptosis/drug effects ; Cell Line, Tumor ; Gene Expression Regulation/drug effects ; Humans ; Immunomodulation ; Interferon Regulatory Factor-1/metabolism ; Interferon-beta/metabolism ; Membrane Proteins/metabolism ; NF-kappa B/metabolism ; Necroptosis/drug effects ; Nucleotides, Cyclic ; Oligopeptides/pharmacology ; Pancreatic Neoplasms/pathology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/metabolism ; Pancreatic Neoplasms
    Chemical Substances Amino Acid Chloromethyl Ketones ; BV6 peptide ; IRF1 protein, human ; Interferon Regulatory Factor-1 ; Membrane Proteins ; NF-kappa B ; Nucleotides, Cyclic ; Oligopeptides ; RNA, Messenger ; STING1 protein, human ; Tumor Necrosis Factor-alpha ; benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone ; cyclic guanosine monophosphate-adenosine monophosphate ; Interferon-beta (77238-31-4)
    Language English
    Publishing date 2021-08-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-021-04014-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis.

    Karlowitz, Rebekka / van Wijk, Sjoerd J L

    The FEBS journal

    2021  

    Abstract: Lytic forms of programmed cell death, like necroptosis, are characterised by cell rupture and the release of cellular contents, often provoking inflammatory responses. In the recent years, necroptosis has been shown to play important roles in human ... ...

    Abstract Lytic forms of programmed cell death, like necroptosis, are characterised by cell rupture and the release of cellular contents, often provoking inflammatory responses. In the recent years, necroptosis has been shown to play important roles in human diseases like cancer, infections and ischaemia/reperfusion injury. Coordinated interactions between RIPK1, RIPK3 and MLKL lead to the formation of a dedicated death complex called the necrosome that triggers MLKL-mediated membrane rupture and necroptotic cell death. Necroptotic cell death is tightly controlled by post-translational modifications, among which especially phosphorylation has been characterised in great detail. Although selective ubiquitination is relatively well-explored in the early initiation stages of necroptosis, the mechanisms and functional consequences of RIPK3 and MLKL ubiquitination for necrosome function and necroptosis are only starting to emerge. This review provides an overview on how site-specific ubiquitination of RIPK3 and MLKL regulates, fine-tunes and reverses the execution of necroptotic cell death.
    Language English
    Publishing date 2021-10-28
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.16255
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 260: 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)

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  5. Article: USP22 regulates APL differentiation via PML-RARα stabilization and IFN repression.

    Kowald, Lisa / Roedig, Jens / Karlowitz, Rebekka / Wagner, Kristina / Smith, Sonja / Juretschke, Thomas / Beli, Petra / Müller, Stefan / van Wijk, Sjoerd J L

    Cell death discovery

    2024  Volume 10, Issue 1, Page(s) 128

    Abstract: Ubiquitin-specific peptidase 22 (USP22) is a deubiquitinating enzyme (DUB) that underlies tumorigenicity, proliferation, cell death and differentiation through deubiquitination of histone and non-histone targets. Ubiquitination determines stability, ... ...

    Abstract Ubiquitin-specific peptidase 22 (USP22) is a deubiquitinating enzyme (DUB) that underlies tumorigenicity, proliferation, cell death and differentiation through deubiquitination of histone and non-histone targets. Ubiquitination determines stability, localization and functions of cell fate proteins and controls cell-protective signaling pathways to surveil cell cycle progression. In a variety of carcinomas, lymphomas and leukemias, ubiquitination regulates the tumor-suppressive functions of the promyelocytic leukemia protein (PML), but PML-specific DUBs, DUB-controlled PML ubiquitin sites and the functional consequences of PML (de)ubiquitination remain unclear. Here, we identify USP22 as regulator of PML and the oncogenic acute promyelocytic leukemia (APL) fusion PML-RARα protein stability and identify a destabilizing role of PML residue K394. Additionally, loss of USP22 upregulates interferon (IFN) and IFN-stimulated gene (ISG) expression in APL and induces PML-RARα stabilization and a potentiation of the cell-autonomous sensitivity towards all-trans retinoic acid (ATRA)-mediated differentiation. Our findings imply USP22-dependent surveillance of PML-RARα stability and IFN signaling as important regulator of APL pathogenesis, with implications for viral mimicry, differentiation and cell fate regulation in other leukemia subtypes.
    Language English
    Publishing date 2024-03-11
    Publishing country United States
    Document type Journal Article
    ISSN 2058-7716
    ISSN 2058-7716
    DOI 10.1038/s41420-024-01894-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING.

    Karlowitz, Rebekka / Stanifer, Megan L / Roedig, Jens / Andrieux, Geoffroy / Bojkova, Denisa / Bechtel, Marco / Smith, Sonja / Kowald, Lisa / Schubert, Ralf / Boerries, Melanie / Cinatl, Jindrich / Boulant, Steeve / van Wijk, Sjoerd J L

    Cell death & disease

    2022  Volume 13, Issue 8, Page(s) 684

    Abstract: Pattern recognition receptors (PRRs) and interferons (IFNs) serve as essential antiviral defense against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Type III IFNs (IFN-λ) exhibit cell-type specific and long-lasting functions in auto- ... ...

    Abstract Pattern recognition receptors (PRRs) and interferons (IFNs) serve as essential antiviral defense against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Type III IFNs (IFN-λ) exhibit cell-type specific and long-lasting functions in auto-inflammation, tumorigenesis, and antiviral defense. Here, we identify the deubiquitinating enzyme USP22 as central regulator of basal IFN-λ secretion and SARS-CoV-2 infections in human intestinal epithelial cells (hIECs). USP22-deficient hIECs strongly upregulate genes involved in IFN signaling and viral defense, including numerous IFN-stimulated genes (ISGs), with increased secretion of IFN-λ and enhanced STAT1 signaling, even in the absence of exogenous IFNs or viral infection. Interestingly, USP22 controls basal and 2'3'-cGAMP-induced STING activation and loss of STING reversed STAT activation and ISG and IFN-λ expression. Intriguingly, USP22-deficient hIECs are protected against SARS-CoV-2 infection, viral replication, and the formation of de novo infectious particles, in a STING-dependent manner. These findings reveal USP22 as central host regulator of STING and type III IFN signaling, with important implications for SARS-CoV-2 infection and antiviral defense.
    MeSH term(s) Antiviral Agents/pharmacology ; COVID-19 ; Humans ; Interferon Type I/genetics ; Interferons/metabolism ; Membrane Proteins/metabolism ; Pandemics ; SARS-CoV-2 ; Ubiquitin Thiolesterase/metabolism ; Interferon Lambda
    Chemical Substances Antiviral Agents ; Interferon Type I ; Membrane Proteins ; STING1 protein, human ; Interferons (9008-11-1) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Usp22 protein, human (EC 3.4.19.12) ; Interferon Lambda
    Language English
    Publishing date 2022-08-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-022-05124-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING

    Karlowitz, Rebekka / Stanifer, Megan L / Roedig, Jens / Andrieux, Geoffroy / Bojkova, Denisa / Smith, Sonja / Kowald, Lisa / Schubert, Ralf / Boerries, Melanie / Cinatl, Jindrich / Boulant, Steeve / van Wijk, Sjoerd JL

    bioRxiv

    Abstract: Pattern recognition receptors (PRRs) and interferons (IFNs) serve as essential antiviral defense against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Type III IFN (IFN-lambda) exhibit cell-type specific and long-lasting functions in ... ...

    Abstract Pattern recognition receptors (PRRs) and interferons (IFNs) serve as essential antiviral defense against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Type III IFN (IFN-lambda) exhibit cell-type specific and long-lasting functions in autoinflammation, tumorigenesis and antiviral defense. Here, we identify the deubiquitinating enzyme USP22 as central regulator of basal IFN-lambda secretion and SARS-CoV-2 infections in human intestinal epithelial cells (hIECs). USP22-deficient hIECs strongly upregulate genes involved in IFN signaling and viral defense, including numerous IFN-stimulated genes (ISGs), with increased secretion of IFN-lambda and enhanced STAT1 signaling, even in the absence of exogenous IFNs or viral infection. Interestingly, USP22 controls basal and cGAMP-induced STING activation and loss of STING reversed STAT activation and ISG and IFN-lambda expression. Intriguingly, USP22-deficient hIECs are protected against SARS-CoV-2 infection, viral replication and the formation of de novo infectious particles, in a STING-dependent manner. These findings reveal USP22 as central host regulator of STING and type III IFN signaling, with important implications for SARS-CoV-2 infection and antiviral defense.
    Keywords covid19
    Language English
    Publishing date 2022-02-02
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2022.02.01.478628
    Database COVID19

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  8. Article ; Online: USP22 controls necroptosis by regulating receptor-interacting protein kinase 3 ubiquitination.

    Roedig, Jens / Kowald, Lisa / Juretschke, Thomas / Karlowitz, Rebekka / Ahangarian Abhari, Behnaz / Roedig, Heiko / Fulda, Simone / Beli, Petra / van Wijk, Sjoerd Jl

    EMBO reports

    2020  Volume 22, Issue 2, Page(s) e50163

    Abstract: Dynamic control of ubiquitination by deubiquitinating enzymes is essential for almost all biological processes. Ubiquitin-specific peptidase 22 (USP22) is part of the SAGA complex and catalyzes the removal of mono-ubiquitination from histones H2A and H2B, ...

    Abstract Dynamic control of ubiquitination by deubiquitinating enzymes is essential for almost all biological processes. Ubiquitin-specific peptidase 22 (USP22) is part of the SAGA complex and catalyzes the removal of mono-ubiquitination from histones H2A and H2B, thereby regulating gene transcription. However, novel roles for USP22 have emerged recently, such as tumor development and cell death. Apart from apoptosis, the relevance of USP22 in other programmed cell death pathways still remains unclear. Here, we describe a novel role for USP22 in controlling necroptotic cell death in human tumor cell lines. Loss of USP22 expression significantly delays TNFα/Smac mimetic/zVAD.fmk (TBZ)-induced necroptosis, without affecting TNFα-mediated NF-κB activation or extrinsic apoptosis. Ubiquitin remnant profiling identified receptor-interacting protein kinase 3 (RIPK3) lysines 42, 351, and 518 as novel, USP22-regulated ubiquitination sites during necroptosis. Importantly, mutation of RIPK3 K518 reduced necroptosis-associated RIPK3 ubiquitination and amplified necrosome formation and necroptotic cell death. In conclusion, we identify a novel role of USP22 in necroptosis and further elucidate the relevance of RIPK3 ubiquitination as crucial regulator of necroptotic cell death.
    MeSH term(s) Apoptosis/genetics ; Humans ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Necroptosis ; Necrosis ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; Ubiquitin Thiolesterase ; Ubiquitination
    Chemical Substances NF-kappa B ; RIPK3 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Usp22 protein, human (EC 3.4.19.12)
    Language English
    Publishing date 2020-12-28
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2020896-0
    ISSN 1469-3178 ; 1469-221X
    ISSN (online) 1469-3178
    ISSN 1469-221X
    DOI 10.15252/embr.202050163
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5433: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 41: Show issues

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