NF-κB/IKK activation by small extracellular vesicles within the SASP

Cellular senescence plays an important role in different biological and pathological conditions. Senescent cells communicate with their microenvironment through a plethora of soluble factors, metalloproteases and extracellular vesicles (EV). Although much is known about the role that soluble factors play in senescence, the downstream signalling pathways activated by EV in senescence is unknown. To address this, we performed a small molecule inhibitor screen and have identified the I kappa B kinases IKK epsilon, IKK alpha and IKK beta as essential for senescence mediated by EV (evSASP). By using pharmacological inhibitors of IKK epsilon, IKK alpha and IKK beta, in addition to CRISPR/Cas9 targeting their respective genes, we find these pathways are important in mediating senescence. In addition, we find that senescence activation is dependent on canonical NF-kappa B transcription factors where siRNA targeting p65 prevent senescence. Importantly, these IKK pathways are also relevant to ageing as knockout of IKKA, IKKB and IKKE avoid the activation of senescence. Altogether, these findings open a new potential line of investigation in the field of senescence by targeting the negative effects of the evSASP independent of particular EV contents.

Automated summary

The study showed that IKK epsilon, IKK alpha, and IKK beta play crucial roles in EV-mediated senescence, while siRNA targeting p65 can prevent senescence activation. Additionally, the IKK pathways are also relevant to aging, as knockout of IKKA, IKKB, and IKKE can avoid the activation of senescence.