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

Abstract

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 IkappaB kinases IKKepsilon, IKKalpha and IKKbeta as essential for senescence mediated by EV (evSASP). By using pharmacological inhibitors of IKKepsilon, IKKalpha and IKKbeta, 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-kappaB 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.