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  1. Article ; Online: RIPK protein kinase family: Atypical lives of typical kinases.

    Cuny, Gregory D / Degterev, Alexei

    Seminars in cell & developmental biology

    2020  Volume 109, Page(s) 96–105

    Abstract: Receptor Interacting Protein Kinases (RIPKs) are a family of Ser/Thr/Tyr kinases whose functions, regulation and pathophysiologic roles have remained an enigma for a long time. In recent years, these proteins garnered significant interest due to their ... ...

    Abstract Receptor Interacting Protein Kinases (RIPKs) are a family of Ser/Thr/Tyr kinases whose functions, regulation and pathophysiologic roles have remained an enigma for a long time. In recent years, these proteins garnered significant interest due to their roles in regulating a variety of host defense functions including control of inflammatory gene expression, different forms of cell death, and cutaneous and intestinal barrier functions. In addition, there is accumulating evidence that while these kinases seemingly follow typical kinase blueprints, their functioning in cells can take forms that are atypical for protein kinases. Lastly, while these kinases generally belong to distinct areas of innate immune regulation, there are emerging overarching themes that may unify the functions of this kinase family. Our review seeks to discuss the biology of RIPKs, and how typical and atypical features of this family informs the activity of a rapidly growing repertoire of RIPK inhibitors.
    MeSH term(s) Humans ; Protein Kinases/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
    Chemical Substances Protein Kinases (EC 2.7.-) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2020-07-27
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1312473-0
    ISSN 1096-3634 ; 1084-9521
    ISSN (online) 1096-3634
    ISSN 1084-9521
    DOI 10.1016/j.semcdb.2020.06.014
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  2. Article ; Online: Chemical Library Screens to Identify Pharmacological Modulators of Necroptosis.

    Saleh, Danish / Degterev, Alexei

    Methods in molecular biology (Clifton, N.J.)

    2018  Volume 1857, Page(s) 19–33

    Abstract: Necroptosis is mediated by the formation of the detergent-insoluble necrosome complex between Ser/Thr kinases RIPK1 and RIPK3, which mediates RIPK3-dependent phosphorylation and activation of the critical necroptosis effector MLKL. Small molecule screens ...

    Abstract Necroptosis is mediated by the formation of the detergent-insoluble necrosome complex between Ser/Thr kinases RIPK1 and RIPK3, which mediates RIPK3-dependent phosphorylation and activation of the critical necroptosis effector MLKL. Small molecule screens have been instrumental in the development of new chemical probes for this pathway. In this chapter, we describe several cellular assays that are readily amendable for the identification of new modulators of necroptosis as well as secondary assays to facilitate initial characterization of the mode of activity of small molecule hits.
    MeSH term(s) Animals ; Apoptosis ; Combinatorial Chemistry Techniques/methods ; Humans ; Necrosis ; Small Molecule Libraries/isolation & purification ; Small Molecule Libraries/pharmacology
    Chemical Substances Small Molecule Libraries
    Language English
    Publishing date 2018-08-22
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-8754-2_3
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  3. Article ; Online: Immunoprecipitation Strategies to Isolate RIPK1/RIPK3 Complexes in Mouse Macrophages.

    Siokas, Ioannis / Zhang, Dingqiang / Poltorak, Alexander / Muendlein, Hayley / Degterev, Alexei

    Current protocols

    2021  Volume 1, Issue 6, Page(s) e156

    Abstract: A large protein complex, containing RIPK1, RIPK3, and caspase-8 and known as Complex II, has emerged as one of the key mediators of cell death downstream from a range of innate immune triggers. This regulatory mechanism plays a prominent role in ... ...

    Abstract A large protein complex, containing RIPK1, RIPK3, and caspase-8 and known as Complex II, has emerged as one of the key mediators of cell death downstream from a range of innate immune triggers. This regulatory mechanism plays a prominent role in macrophages, where Complex II has been linked to apoptosis, pyroptosis, and necroptosis as well as the enhancement of inflammatory gene expression. Although core components of this complex are fairly well understood, more subtle proteomic changes that determine the direction of a response once the complex is assembled remain much less clear. In addition, Complex II components undergo a wealth of post-translational changes that modify the functions of the complex components. This necessitates development of robust and efficient methods of isolating Complex II for further interrogation of its composition and the post-translational modifications of its components. This article describes several methods that we have developed for Complex II isolation, which can be used to obtain complementary information about this signaling mechanism. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Isolation of Complex II in necroptotic and pyroptotic macrophages using FADD immunoprecipitation Basic Protocol 2: Isolation of the complexes formed by the conditionally expressed 3XFLAG-RIPK1 protein Alternate Protocol: Alternative methods of immunoprecipitation of RIPK1 and other Complex-II-related factors Support Protocol: Generation of stable macrophage cell lines using lentiviral expression Basic Protocol 3: Use of proximity labeling to identify necrosome components in the detergent-insoluble fraction of the cell lysates.
    MeSH term(s) Animals ; Apoptosis ; Immunoprecipitation ; Macrophages/metabolism ; Mice ; Necroptosis ; Proteomics ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics
    Chemical Substances Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk1 protein, mouse (EC 2.7.11.1) ; Ripk3 protein, mouse (EC 2.7.11.1)
    Language English
    Publishing date 2021-06-09
    Publishing country United States
    Document type Journal Article
    ISSN 2691-1299
    ISSN (online) 2691-1299
    DOI 10.1002/cpz1.156
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  4. Article: Emerging Roles for RIPK1 and RIPK3 in Pathogen-Induced Cell Death and Host Immunity.

    Saleh, Danish / Degterev, Alexei

    Current topics in microbiology and immunology

    2017  Volume 403, Page(s) 37–75

    Abstract: Receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3 ) are homologous serine-threonine kinases that were recognized for their roles in directing programmed necrotic cell death or necroptosis under a broad range of pathologic settings. Emerging ... ...

    Abstract Receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3 ) are homologous serine-threonine kinases that were recognized for their roles in directing programmed necrotic cell death or necroptosis under a broad range of pathologic settings. Emerging evidence suggests new physiologic roles for RIPK1 and RIPK3 in mediating cell death of innate immune responses. Our review discusses current evidence on the mechanisms and the impact of RIPK1- and/or RIPK3-dependent cell death in responses to a variety of viral and bacterial pathogens. Furthermore, the discussion also summarizes emerging roles for RIPK1 and RIPK3 in other facets of host immunity, including the maintenance of epithelial barrier function and pro-inflammatory processes that may, in some cases, manifest independent of cell death. Finally, we briefly consider the therapeutic opportunities in targeting RIPK1- and RIPK3-dependent processes in infection and immunity.
    MeSH term(s) Animals ; Cell Death/immunology ; Host-Pathogen Interactions/immunology ; Humans ; Immunity/immunology ; Receptor-Interacting Protein Serine-Threonine Kinases/immunology
    Chemical Substances Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2017
    Publishing country Germany
    Document type Journal Article ; Review
    ISSN 0070-217X
    ISSN 0070-217X
    DOI 10.1007/82_2015_449
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  5. Article ; Online: Targeting RIPK1 for the treatment of human diseases.

    Degterev, Alexei / Ofengeim, Dimitry / Yuan, Junying

    Proceedings of the National Academy of Sciences of the United States of America

    2019  Volume 116, Issue 20, Page(s) 9714–9722

    Abstract: RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This was supported by extensive studies which demonstrated that RIPK1 is a key mediator of ... ...

    Abstract RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This was supported by extensive studies which demonstrated that RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways. Furthermore, human genetic evidence has linked the dysregulation of RIPK1 to the pathogenesis of ALS as well as other inflammatory and neurodegenerative diseases. Importantly, unique allosteric small-molecule inhibitors of RIPK1 that offer high selectivity have been developed. These molecules can penetrate the blood-brain barrier, thus offering the possibility to target neuroinflammation and cell death which drive various neurologic conditions including Alzheimer's disease, ALS, and multiple sclerosis as well as acute neurological diseases such as stroke and traumatic brain injuries. We discuss the current understanding of RIPK1 regulatory mechanisms and emerging evidence for the pathological roles of RIPK1 in human diseases, especially in the context of the central nervous systems.
    MeSH term(s) Apoptosis ; Central Nervous System Diseases/drug therapy ; Drug Development ; Gene Expression ; Humans ; Inflammation/metabolism ; Molecular Targeted Therapy ; Necroptosis ; Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances Tumor Necrosis Factor-alpha ; RIPK1 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2019-05-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1901179116
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  6. Article ; Online: International and Regional Studies

    D A. Degterev

    Сравнительная политика, Vol 12, Iss 4, Pp 82-

    Towards a «Seamless» Methodology of Analysis. Discussing the book: Logika novoy miroustroitel'noy arkhitektoniki i strategii derzhav (The Logic of the New World Architectonics and the Strategies of the Powers). Ed. by Alexei D. Voskressenski. Moscow: Strategicheskiye izyskaniya, 2021. 576 p.

    2022  Volume 97

    Abstract: ... by examples from the collective monograph, ed. by Alexei D. Voskressenski “The Logic of the New World ...

    Abstract The paper is dedicated to the key methodological problems of international and regional studies and the prospects for the formation of a unifi ed, «seamless» methodology. The author's refl ections are illustrated by examples from the collective monograph, ed. by Alexei D. Voskressenski “The Logic of the New World Architectonics and the Strategies of the Powers” (2021). At the fi rst stage, the question of the levels of analysis in international studies is investigated with a special emphasis on the systemic level, as well as the practical diffi culties of decomposition of international political situations, taking into account the high density of social ties. The applied value of network analysis and event analysis is shown. The phenomenon of transregionalism, which is of great importance for international economic relations, is considered from a network point of view. Methodological tools for the analysis of trans-regional institutions are presented as well. Much attention is paid to the organismic concept of the general theory of the system and its adaptation to the IR system. The practical use of this concept in organizing situational analyzes of international processes is shown. The regional level of analysis and the place of the “middle-level powers” in the world system are revealed through the prism of an agent-structural “matryoshka” (nested model) – agent-structural problem at different levels ofanalysis. The limits and possibilities of application of the complexity theory in the analysis of IR are explored. Special attention is paid to the concept of complex interdependence of R. Keohane and J. Nye, which, according to the author, adequately refl ects modern IR and is the key to understanding the formation of zones of infl uence of great powers in world politics. Finally, the work reveals the normative component of IR theory and shows an increasing popularity of non-Western IR theories in the last few years. The normativity in regional studies is explored as well and particular cases of the application ...
    Keywords теория международных отношений ; незападные тмо ; прикладной анализ ; системное моделирование ; ситуационные анализы ; сетевой анализ ; ивент-анализ ; трансрегионализм ; организмический подход ; агент-структурная проблема ; теория сложности ; комплексная взаимозависимость ; Political science (General) ; JA1-92
    Subject code 320
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Jurist, Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Generation of small molecules to interfere with regulated necrosis.

    Degterev, Alexei / Linkermann, Andreas

    Cellular and molecular life sciences : CMLS

    2016  Volume 73, Issue 11-12, Page(s) 2251–2267

    Abstract: Interference with regulated necrosis for clinical purposes carries broad therapeutic relevance and, if successfully achieved, has a potential to revolutionize everyday clinical routine. Necrosis was interpreted as something that no clinician might ever ... ...

    Abstract Interference with regulated necrosis for clinical purposes carries broad therapeutic relevance and, if successfully achieved, has a potential to revolutionize everyday clinical routine. Necrosis was interpreted as something that no clinician might ever be able to prevent due to the unregulated nature of this form of cell death. However, given our growing understanding of the existence of regulated forms of necrosis and the roles of key enzymes of these pathways, e.g., kinases, peroxidases, etc., the possibility emerges to identify efficient and selective small molecule inhibitors of pathologic necrosis. Here, we review the published literature on small molecule inhibition of regulated necrosis and provide an outlook on how combination therapy may be most effective in treatment of necrosis-associated clinical situations like stroke, myocardial infarction, sepsis, cancer and solid organ transplantation.
    MeSH term(s) Animals ; Apoptosis/physiology ; Cyclohexylamines/pharmacology ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; Imidazoles/pharmacology ; Mice ; Necrosis/drug therapy ; Necrosis/pathology ; Organic Chemicals/pharmacology ; Phenylenediamines/pharmacology ; Protein Kinases/metabolism ; Pyridazines/pharmacology ; Quinoxalines/pharmacology ; Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors ; Spiro Compounds/pharmacology ; Sulfones/pharmacology
    Chemical Substances Cyclohexylamines ; Heterocyclic Compounds, 4 or More Rings ; Imidazoles ; NecroX-5 ; Organic Chemicals ; Phenylenediamines ; Pyridazines ; Quinoxalines ; Spiro Compounds ; Sulfones ; ferrostatin-1 ; liproxstatin-1 ; necrox-7 ; ponatinib (4340891KFS) ; MLKL protein, human (EC 2.7.-) ; Protein Kinases (EC 2.7.-) ; RIPK1 protein, human (EC 2.7.11.1) ; RIPK3 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2016-04-05
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-016-2198-x
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  8. Article ; Online: Targeting RIPK1,2,3 to combat inflammation.

    Bullock, Alex N / Degterev, Alexei

    Oncotarget

    2015  Volume 6, Issue 33, Page(s) 34057–34058

    MeSH term(s) Humans ; Immunity, Innate/immunology ; Inflammation/immunology ; Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
    Chemical Substances RIPK1 protein, human (EC 2.7.11.1) ; RIPK2 protein, human (EC 2.7.11.1) ; RIPK3 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinase 2 (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2015-10-27
    Publishing country United States
    Document type Editorial
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.6106
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  9. Article ; Online: ZBP1 promotes inflammatory responses downstream of TLR3/TLR4 via timely delivery of RIPK1 to TRIF.

    Muendlein, Hayley I / Connolly, Wilson M / Magri, Zoie / Jetton, David / Smirnova, Irina / Degterev, Alexei / Balachandran, Siddharth / Poltorak, Alexander

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 24, Page(s) e2113872119

    Abstract: ZBP1 is widely recognized as a mediator of cell death for its role in initiating necroptotic, apoptotic, and pyroptotic cell death pathways in response to diverse pathogenic infection. Herein, we characterize an unanticipated role for ZBP1 in promoting ... ...

    Abstract ZBP1 is widely recognized as a mediator of cell death for its role in initiating necroptotic, apoptotic, and pyroptotic cell death pathways in response to diverse pathogenic infection. Herein, we characterize an unanticipated role for ZBP1 in promoting inflammatory responses to bacterial lipopolysaccharide (LPS) or double-stranded RNA (dsRNA). In response to both stimuli, ZBP1 promotes the timely delivery of RIPK1 to the Toll-like receptor (TLR)3/4 adaptor TRIF and M1-ubiquitination of RIPK1, which sustains activation of inflammatory signaling cascades downstream of RIPK1. Strikingly, ZBP1-mediated regulation of these pathways is important in vivo, as Zbp1−/− mice exhibited resistance to LPS-induced septic shock, revealed by prolonged survival and delayed onset of hypothermia due to decreased inflammatory responses and subsequent cell death. Further findings revealed that ZBP1 promotes sustained inflammatory responses by mediating the kinetics of proinflammatory “TRIFosome” complex formation, thus having a profound impact downstream of TLR activation. Given the well-characterized role of ZBP1 as a viral sensor, our results exemplify previously unappreciated crosstalk between the pathways that regulate host responses to bacteria and viruses, with ZBP1 acting as a crucial bridge between the two.
    MeSH term(s) Adaptor Proteins, Vesicular Transport/metabolism ; Animals ; Inflammation/metabolism ; Lipopolysaccharides/toxicity ; Mice ; RNA, Double-Stranded ; RNA-Binding Proteins/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Toll-Like Receptor 3/metabolism ; Toll-Like Receptor 4/metabolism
    Chemical Substances Adaptor Proteins, Vesicular Transport ; Lipopolysaccharides ; RNA, Double-Stranded ; RNA-Binding Proteins ; TLR3 protein, mouse ; Tlr4 protein, mouse ; Toll-Like Receptor 3 ; Toll-Like Receptor 4 ; Zbp1 protein, mouse ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Ripk1 protein, mouse (EC 2.7.11.1)
    Language English
    Publishing date 2022-06-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2113872119
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  10. Article ; Online: Caspase-Dependent Suppression of Type I Interferon Signaling Promotes Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication.

    Tabtieng, Tate / Degterev, Alexei / Gaglia, Marta M

    Journal of virology

    2018  Volume 92, Issue 10

    Abstract: An important component of lytic infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is the ability of the virus to evade the innate immune response, specifically type I interferon (IFN) responses that are triggered by recognition of viral nucleic ...

    Abstract An important component of lytic infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is the ability of the virus to evade the innate immune response, specifically type I interferon (IFN) responses that are triggered by recognition of viral nucleic acids. Inhibition of type I IFN responses by the virus promotes viral replication. Here, we report that KSHV uses a caspase-dependent mechanism to block type I IFN, in particular IFN-β, responses during lytic infection. Inhibition of caspases during KSHV reactivation resulted in increased TBK1/IKKε-dependent phosphorylation of IRF3 as well as elevated levels of IFN-β transcription and secretion. The increased secretion of IFN-β upon caspase inhibition reduced viral gene expression, viral DNA replication, and virus production. Blocking IFN-β production or signaling restored viral replication. Overall, our results show that caspase-mediated regulation of pathogen sensing machinery is an important mechanism exploited by KSHV to evade innate immune responses.
    MeSH term(s) Caspases/genetics ; Caspases/metabolism ; DNA Replication ; DNA, Viral/biosynthesis ; DNA, Viral/genetics ; HeLa Cells ; Herpesvirus 8, Human/physiology ; Humans ; Interferon Regulatory Factor-3/genetics ; Interferon Regulatory Factor-3/metabolism ; Interferon-beta/genetics ; Interferon-beta/metabolism ; Signal Transduction ; Virus Replication
    Chemical Substances DNA, Viral ; IRF3 protein, human ; Interferon Regulatory Factor-3 ; Interferon-beta (77238-31-4) ; Caspases (EC 3.4.22.-)
    Language English
    Publishing date 2018-04-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00078-18
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