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NF-κB/IKK activation by small extracellular vesicles within the SASP.
Juan Antonio Fafián-Labora1, Ana O'Loghlen1
1Epigenetics & Cellular Senescence Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Aging Cell
|June 29, 2021
Summary
Researchers identified IκB kinases (IKKε, IKKα, IKKβ) as key mediators of senescence triggered by extracellular vesicles (EVs). Targeting these pathways may offer new strategies against aging and disease.
Area of Science:
- Cellular biology
- Molecular biology
- Immunology
Background:
- Cellular senescence is crucial in biological and pathological processes.
- Senescent cells secrete factors (evSASP) via extracellular vesicles (EVs), impacting their microenvironment.
- Downstream signaling pathways activated by EV-mediated senescence remain largely unknown.
Purpose of the Study:
- To identify signaling pathways mediating senescence induced by extracellular vesicles (EVs).
- To investigate the role of IκB kinases (IKKs) in EV-mediated senescence.
Main Methods:
- Conducted a small molecule inhibitor screen.
- Utilized pharmacological inhibitors and CRISPR/Cas9 gene targeting for IKKε, IKKα, and IKKβ.
- Employed siRNA to target p65 (NF-κB transcription factor).
Main Results:
- Identified IKKε, IKKα, and IKKβ as essential for EV-mediated senescence (evSASP).
- Demonstrated that senescence activation depends on canonical NF-κB transcription factors, including p65.
- Showed that knockout of IKKA, IKKB, and IKKE prevents senescence activation, highlighting relevance to aging.
Conclusions:
- Uncovered a novel signaling axis involving IKKs and NF-κB in EV-mediated senescence.
- These findings suggest targeting IKK pathways as a potential strategy to mitigate negative effects of evSASP.
- Opens new avenues for research into senescence and aging, independent of specific EV cargo.
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