UFMylation maintains YAP stability to promote vascular endothelial cell senescence

Endothelial cell senescence is an accomplice for vascular aging, which leads to cardiovascular diseases (CVD). Evidences showed that Hippo- Yes-associated protein (YAP) signaling pathway plays an essential role in aging-associated CVD. However, the exact role of YAP protein in endothelial cell senescence remains not fully clear. Here, we reported that YAP was elevated in senescent human umbilical vein endothelial cells (HUVECs) and inhibition of YAP by either specific siRNAs or inhibitor Verteporfin could attenuate HUVECs senescence. In contrast, overexpression of YAP induces cell senescence. Besides, we found that UFMylation activity and YAP were both elevated in senescent cells. Mechanistically, we found that UFMylation, a newly identified ubiquitin-like modification with essential biological functions, maintains the stability of YAP and further found that YAP is a substrate for UFMylation. Importantly, we found that compound 8.5, an inhibitor of E1 of UFMylation, can attenuate cell senescence with reduced YAP protein and alleviate vascular aging and improve cardiac function in aged mice. Therefore, compound 8.5 may be a potential small molecule for delaying vascular aging. Together, our finding provides molecular mechanism by which UFMylation maintains YAP stability and exerts an important role in promoting cell senescence, and identified that a previously unrecognized UFMylation is a potential therapeutic target for anti-aging.