Artículo del mes
septiembre 2021

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

Referencia artículo:
Fafián-Labora, J.A., & O’Loghlen A. (2021). NF- κB/IKK activation by small extracellular vesicles within the SASP. Aging Cell, 20, e13426.
En este estudio se descubrio que la activación de la ruta de NF-κB/IKK es uno de los mecanismos de transmisión de senescencia paracrina celular a través de pequeñas vesículas extracelulares. Para ello, empleamos inhibidores farmacológicos y modificación genética empleando Crispr/Cas9 de los algunos de los components de la ruta de NF-kB (IKKε, IKKα and IKKβ) los cuales bloquean la senescencia paracrine mediada por las vesiculas. Estas rutas se regulan tambien durante de envejecimiento y enfermedades asociadas a la edad.
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 IκB kinases IKKε, IKKα and IKKβ as essential for senescence mediated by EV (evSASP). By using pharmacological inhibitors of IKKε, IKKα and IKKβ, 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-κB 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.
Sobre el grupo investigador