Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair

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Abstract

Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell death can interfere with such programs and cause organ failure. Cellular FLICE-like inhibitory protein (cFLIP) is a crucial regulator of cell death and a substrate of Caspase-8. However, the physiological role of cFLIP cleavage by Caspase-8 remains elusive. Here, we found an essential role for cFLIP cleavage in restraining cell death in different pathophysiological scenarios. Mice expressing a cleavage-resistant cFLIP mutant, Cflip ^D377A , exhibited increased sensitivity to severe acute respiratory syndrome coronavirus (SARS-CoV)–induced lethality, impaired skin wound healing, and increased tissue damage caused by Sharpin deficiency. In vitro, abrogation of cFLIP cleavage sensitizes cells to tumor necrosis factor(TNF)–induced necroptosis and apoptosis by favoring complex-II formation. Mechanistically, the cell death–sensitizing effect of the D377A mutation depends on glutamine-469. These results reveal a crucial role for cFLIP cleavage in controlling the amplitude of cell death responses occurring upon tissue stress to ensure the execution of repair programs.

Abstract

cFLIP cleavage acts as a molecular brake on cell death and is essential for the ability of tissues to overcome damage.

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Most cited references 67

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Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

Olivier Micheau, Jurg Tschopp (2003)

Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.

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Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes

Rajendra Karki, Bhesh Sharma, Shraddha Tuladhar … (2020)

COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by pyroptosis, apoptosis, and necroptosis (PANoptosis). Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD–mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.

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TNF biology, pathogenic mechanisms and emerging therapeutic strategies.

George Kalliolias, Lionel B Ivashkiv (2016)

TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce new concepts for the development of therapeutics for TNF-mediated diseases. The model of TNF receptor signalling has been extended to include linear ubiquitination and the formation of distinct signalling complexes that are linked with different functional outcomes, such as inflammation, apoptosis and necroptosis. Our understanding of TNF-induced gene expression has been enriched by the discovery of epigenetic mechanisms and concepts related to cellular priming, tolerization and induction of 'short-term transcriptional memory'. Identification of distinct homeostatic or pathogenic TNF-induced signalling pathways has introduced the concept of selectively inhibiting the deleterious effects of TNF while preserving its homeostatic bioactivities for therapeutic purposes. In this Review, we present molecular mechanisms underlying the roles of TNF in homeostasis and inflammatory disease pathogenesis, and discuss novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases.

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Author and article information

Contributors

Kristel Martinez Lagunas:

ORCID: https://orcid.org/0000-0002-8306-6982

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Deniz Pinar Savcigil:

ORCID: https://orcid.org/0000-0002-9217-5582

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Matea Zrilic:

ORCID: https://orcid.org/0000-0001-5548-9681

Role: InvestigationRole: MethodologyRole: Visualization

Carlos Carvajal Fraile:

ORCID: https://orcid.org/0000-0002-5354-9123

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Validation

Andrew Craxton:

ORCID: https://orcid.org/0000-0002-5957-9251

Role: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draft

Emily Self:

ORCID: https://orcid.org/0000-0003-2203-6947

Role: Investigation

Iratxe Uranga-Murillo:

ORCID: https://orcid.org/0000-0001-8411-984X

Role: InvestigationRole: MethodologyRole: ValidationRole: Visualization

Diego de Miguel:

ORCID: https://orcid.org/0000-0002-8486-8514

Role: ConceptualizationRole: Investigation

Maykel Arias: Role: InvestigationRole: Writing - original draftRole: Writing - review & editing

Sebastian Willenborg:

ORCID: https://orcid.org/0000-0002-0840-227X

Role: InvestigationRole: Methodology

Michael Piekarek:

ORCID: https://orcid.org/0009-0008-9030-8696

Role: InvestigationRole: Methodology

Marie Christine Albert: Role: InvestigationRole: MethodologyRole: Resources

Kalvin Nugraha:

ORCID: https://orcid.org/0000-0002-3063-4827

Role: Formal analysisRole: InvestigationRole: Validation

Ina Lisewski:

ORCID: https://orcid.org/0009-0001-5559-8404

Role: InvestigationRole: Validation

Erika Janakova:

ORCID: https://orcid.org/0009-0007-7607-104X

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Validation

Natalia Igual: Role: InvestigationRole: Methodology

Wulf Tonnus:

ORCID: https://orcid.org/0000-0002-9728-1413

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Ximena Hildebrandt:

ORCID: https://orcid.org/0000-0001-6930-203X

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: Writing - review & editing

Mohammed Ibrahim:

ORCID: https://orcid.org/0000-0003-4289-2687

Role: Formal analysisRole: InvestigationRole: MethodologyRole: Visualization

Marlies Ballegeer:

ORCID: https://orcid.org/0000-0002-4914-7455

Role: Investigation

Xavier Saelens:

ORCID: https://orcid.org/0000-0002-3861-6965

Role: ConceptualizationRole: MethodologyRole: Project administrationRole: Supervision

Andrew Kueh: Role: Methodology

Pascal Meier:

ORCID: https://orcid.org/0000-0003-2760-6523

Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: ValidationRole: Writing - original draftRole: Writing - review & editing

Andreas Linkermann:

ORCID: https://orcid.org/0000-0001-6287-9725

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: Supervision

Julian Pardo:

ORCID: https://orcid.org/0000-0003-0154-0730

Role: ConceptualizationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing

Sabine Eming:

ORCID: https://orcid.org/0000-0001-8485-3921

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Henning Walczak:

ORCID: https://orcid.org/0000-0002-6312-4591

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: Supervision

Marion MacFarlane:

ORCID: https://orcid.org/0000-0001-7886-1159

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Nieves Peltzer:

ORCID: https://orcid.org/0000-0002-4134-5852

Role: ConceptualizationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Alessandro Annibaldi:

ORCID: https://orcid.org/0000-0002-0346-4340

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: July 2023

Publication date (Electronic, pub): 26 July 2023

Volume: 9

Issue: 30

Electronic Location Identifier: eadg2829

Affiliations

[ ¹ ]Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Strasse 21, 50931, Cologne, Germany.

[ ² ]MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK.

[ ³ ]Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.

[ ⁴ ]Department of Microbiology, Radiology, Pediatry and Public Health, University of Zaragoza, Zaragoza, Spain.

[ ⁵ ]CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.

[ ⁶ ]Department of Dermatology, University of Cologne, 50937 Cologne, Germany.

[ ⁷ ]Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.

[ ⁸ ]Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany.

[ ⁹ ]Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.

[ ¹⁰ ]Biotechnology Center, Technische Universität Dresden, Dresden, Germany.

[ ¹¹ ]Department of Translational Genomics, University of Cologne, Weyertal 115b, 50931 Köln, Germany.

[ ¹² ]VIB-UGent Center for Medical Biotechnology, VIB, B-9052 Ghent, Belgium.

[ ¹³ ]Department of Biochemistry and Microbiology, Ghent University, B-9000 Ghent, Belgium.

[ ¹⁴ ]Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

[ ¹⁵ ]Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.

[ ¹⁶ ]The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

[ ¹⁷ ]Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.

[ ¹⁸ ]Institute of Zoology, Developmental Biology Unit, University of Cologne, 50674 Cologne, Germany.

[ ¹⁹ ]Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College, London WC1E 6BT, UK.

Author notes

[* ]Corresponding author. Email: a.annibaldi@ 123456uni-koeln.de

[†]

These authors contributed equally to this work.

Author information

Kristel Martinez Lagunas https://orcid.org/0000-0002-8306-6982

Deniz Pinar Savcigil https://orcid.org/0000-0002-9217-5582

Matea Zrilic https://orcid.org/0000-0001-5548-9681

Carlos Carvajal Fraile https://orcid.org/0000-0002-5354-9123

Andrew Craxton https://orcid.org/0000-0002-5957-9251

Emily Self https://orcid.org/0000-0003-2203-6947

Iratxe Uranga-Murillo https://orcid.org/0000-0001-8411-984X

Diego de Miguel https://orcid.org/0000-0002-8486-8514

Sebastian Willenborg https://orcid.org/0000-0002-0840-227X

Michael Piekarek https://orcid.org/0009-0008-9030-8696

Kalvin Nugraha https://orcid.org/0000-0002-3063-4827

Ina Lisewski https://orcid.org/0009-0001-5559-8404

Erika Janakova https://orcid.org/0009-0007-7607-104X

Wulf Tonnus https://orcid.org/0000-0002-9728-1413

Ximena Hildebrandt https://orcid.org/0000-0001-6930-203X

Mohammed Ibrahim https://orcid.org/0000-0003-4289-2687

Marlies Ballegeer https://orcid.org/0000-0002-4914-7455

Xavier Saelens https://orcid.org/0000-0002-3861-6965

Pascal Meier https://orcid.org/0000-0003-2760-6523

Andreas Linkermann https://orcid.org/0000-0001-6287-9725

Julian Pardo https://orcid.org/0000-0003-0154-0730

Sabine Eming https://orcid.org/0000-0001-8485-3921

Henning Walczak https://orcid.org/0000-0002-6312-4591

Marion MacFarlane https://orcid.org/0000-0001-7886-1159

Nieves Peltzer https://orcid.org/0000-0002-4134-5852

Alessandro Annibaldi https://orcid.org/0000-0002-0346-4340

Article

Publisher ID: adg2829

DOI: 10.1126/sciadv.adg2829

PMC ID: 10371024

PubMed ID: 37494451

SO-VID: e0b1a6a5-d7ab-4fd9-b7d5-8b48299aaf72

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 09 January 2023

Date accepted : 22 June 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100005156, Alexander von Humboldt-Stiftung;

Funded by: FundRef http://dx.doi.org/10.13039/100005930, ASCRS Research Foundation;

Award ID: AN 1717/1-1

Funded by: FundRef http://dx.doi.org/10.13039/100005930, ASCRS Research Foundation;

Funded by: FundRef http://dx.doi.org/10.13039/100006301, Center for International Business Education and Research, University of Illinois at Urbana-Champaign;

Award ID: PID2020-113963RBI00

Funded by: FundRef http://dx.doi.org/10.13039/100006301, Center for International Business Education and Research, University of Illinois at Urbana-Champaign;

Funded by: FundRef http://dx.doi.org/10.13039/100007472, University of Kentucky;

Award ID: A17341

Funded by: FundRef http://dx.doi.org/10.13039/501100011033, Agencia Estatal de Investigación;

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Award ID: 214342/Z/18/Z

Funded by: FundRef http://dx.doi.org/10.13039/501100007155, Medical Research Council Canada;

Award ID: MR/S00811X/1

Funded by: FundRef http://dx.doi.org/10.13039/501100007155, Medical Research Council Canada;

Award ID: 00025/4

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;

Funded by: FundRef http://dx.doi.org/10.13039/501100008530, European Regional Development Fund;

Funded by: FundRef http://dx.doi.org/10.13039/501100011033, Agencia Estatal de Investigación;

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Funded by: FundRef http://dx.doi.org/10.13039/501100007155, Medical Research Council Canada;

Funded by: FundRef http://dx.doi.org/10.13039/100012573, MicroResearch;

Funded by: FundRef http://dx.doi.org/10.13039/100007472, University of Kentucky;

Funded by: Center for Molecular Medicine Cologne (CMMC);

Award ID: Junior research group program

Funded by: Wellcome Trust Investigator Award;

Award ID: 214342/Z/18/Z

Funded by: Molecular Medicine Cologne CMMC Junior;

Funded by: Manchot Foundation;