Epigenetics & Cellular Senescence Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Aging Cell. 2021 Jul;20(7):e13426. doi: 10.1111/acel.13426. Epub 2021 Jun 29.
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.
细胞衰老在不同的生物学和病理学条件下起着重要作用。衰老细胞通过大量可溶性因子、金属蛋白酶和细胞外囊泡（EV）与微环境进行通讯。尽管人们已经了解了可溶性因子在衰老中的作用，但 EV 在衰老中激活的下游信号通路尚不清楚。为了解决这个问题，我们进行了小分子抑制剂筛选，发现 IκB 激酶 IKKε、IKKα 和 IKKβ 是 EV（evSASP）介导的衰老所必需的。通过使用 IKKε、IKKα 和 IKKβ 的药理学抑制剂，以及针对它们各自基因的 CRISPR/Cas9，我们发现这些途径在介导衰老中很重要。此外，我们发现衰老的激活依赖于经典的 NF-κB 转录因子，其中靶向 p65 的 siRNA 可阻止衰老。重要的是，这些 IKK 途径与衰老也有关，因为 IKKA、IKKB 和 IKKE 的敲除可避免衰老的激活。总之，这些发现通过靶向 evSASP 的负面效应，为衰老领域的研究开辟了一条新的潜在途径，而与特定的 EV 内容无关。
