Skip to content
DraconiticResearch
Search Sources API
197,768 studies31 sourcesUpdated 12 min ago
Peer-reviewedCC BY 4.0Proceedings of the National Academy of Sciences of the United States of America

c-FLIP loss links arrest of gene expression to TNFα-dependent antiviral guard immunity

  • Matthew Sonnett1
  • Sanne Boersma1
  • Madeline E. Ward1
  • Laura C. Van Eyndhoven2
  • Edoardo Centofanti1
  • Max Brambach1
  • Changhong Zhou3
  • David M. Knipe3
  • Arjun Raj2,4
  • Alon Oyler-Yaniv1
  • Jennifer Oyler-Yaniv1
4 affiliations
  1. 1The Department of Systems Biology, Harvard Medical School, Boston, MA 02115
  2. 2The Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104
  3. 3Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115
  4. 4The Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
Read full textDOICite

Abstract

Cells sense infection through dedicated receptors, yet these surveillance pathways are often subverted by pathogen-encoded virulence factors. Guard immunity provides complementary defense by rapidly killing infected cells in response to infection induced stress. However, the symptoms of infection frequently resemble noninfectious stress, raising the question of how they are distinguished. Using quantitative transcriptomics, proteomics, and global translation measurements during viral infections in vitro and in vivo, we show that infection globally suppresses host gene expression and prevents direct antiviral responses. However, the resulting proteostatic stress does not activate guard immunity unless tumor necrosis factor-α (TNFα) is present. We identify the anti-apoptotic protein c-FLIP as a guard for gene expression integrity: its loss sensitizes cells to TNFα, triggering cell death and limiting viral spread. Modeling demonstrates that TNFα and c-FLIP loss function as a biological AND-gate, providing specificity and speed. These findings show how cells integrate internal stress signals with external inflammatory cues to improve the fidelity of death decisions, and how this circuitry may misfire during noninfectious inflammation.

Related

  1. The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation
    Pham Thuy Tien Vo, Julien Cicero, Zichen Wang +17
    Cell ReportsPeer-reviewedCC BY 4.0ImmunologyCrossref
  2. The orphan receptor IL-17RD is a negative regulator of RIG-I-like receptor-dependent antiviral innate immunity and restrains SARS-CoV-2-induced lung inflammation
    F. El-Mortada, J. Roy, C. Girondel +11
    bioRxivPreprintCC BY-NC-NDFull textMicrobiologybioRxiv
  3. Antiviral immunity via telomerase-like reverse transcription in bacteria
    Stephen Tang, Josephine L. Ramirez, Qixiang He +11
    NaturePeer-reviewedLicence not statedFull text9 citedEcologyMicrobiologyOpenAlex
  4. High-Throughput Screening Identifies Proteasome Inhibitors as Potentiators of Type III Interferon JAK-STAT Signaling and Antiviral Immunity
    J.-P. Parisien, C. O Leary, S. Shabani +5
    bioRxivPreprintCC BYFull textImmunologybioRxiv
  5. EV-B 3D polymerase remodels viral populations through 5′UTR recombination to subvert cardiac antiviral innate immunity
    Marie Glenet, Laetitia Heng, Anne-Laure Lebreil +4
    PLoS PathogensPeer-reviewedCC BY 4.0Full textGeneral biologyHAL

Cite

BibTeXRIS
BibTeX
@article{sonnett2026cflip,
  title = {{c-FLIP loss links arrest of gene expression to TNFα-dependent antiviral guard immunity}},
  author = {Matthew Sonnett and Sanne Boersma and Madeline E. Ward and Laura C. Van Eyndhoven and Edoardo Centofanti and Max Brambach and Changhong Zhou and David M. Knipe and Arjun Raj and Alon Oyler-Yaniv and Jennifer Oyler-Yaniv},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2600336123},
  url = {https://doi.org/10.1073/pnas.2600336123},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - c-FLIP loss links arrest of gene expression to TNFα-dependent antiviral guard immunity
AU  - Matthew Sonnett
AU  - Sanne Boersma
AU  - Madeline E. Ward
AU  - Laura C. Van Eyndhoven
AU  - Edoardo Centofanti
AU  - Max Brambach
AU  - Changhong Zhou
AU  - David M. Knipe
AU  - Arjun Raj
AU  - Alon Oyler-Yaniv
AU  - Jennifer Oyler-Yaniv
PY  - 2026
DA  - 2026/10/22
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2600336123
UR  - https://doi.org/10.1073/pnas.2600336123
AB  - Cells sense infection through dedicated receptors, yet these surveillance pathways are often subverted by pathogen-encoded virulence factors. Guard immunity provides complementary defense by rapidly killing infected cells in response to infection induced stress. However, the symptoms of infection frequently resemble noninfectious stress, raising the question of how they are distinguished. Using quantitative transcriptomics, proteomics, and global translation measurements during viral infections in vitro and in vivo, we show that infection globally suppresses host gene expression and prevents direct antiviral responses. However, the resulting proteostatic stress does not activate guard immunity unless tumor necrosis factor-α (TNFα) is present. We identify the anti-apoptotic protein c-FLIP as a guard for gene expression integrity: its loss sensitizes cells to TNFα, triggering cell death and limiting viral spread. Modeling demonstrates that TNFα and c-FLIP loss function as a biological AND-gate, providing specificity and speed. These findings show how cells integrate internal stress signals with external inflammatory cues to improve the fidelity of death decisions, and how this circuitry may misfire during noninfectious inflammation.
SN  - 0027-8424
SN  - 1091-6490
ER  -