E3 UFM1-protein ligase 1
protein ufmylation
UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.
p53 is the most intensively studied tumour suppressor<sup>1</sup>. The regulation of p53 homeostasis is essential for its tumour-suppressive function<sup>2,3</sup>. Although p53 is regulated by an array of post-translational modifications, both during normal homeostasis and in stress-induced responses<sup>2-4</sup>, how p53 maintains its homeostasis remains unclear. UFMylation is a recently identified ubiquitin-like modification with essential biological functions<sup>5-7</sup>. Deficiency in this modification leads to embryonic lethality in mice and disease in humans<sup>8-12</sup>. Here, we report that p53 can be covalently modified by UFM1 and that this modification stabilizes p53 by antagonizing its ubiquitination and proteasome degradation. Mechanistically, UFL1, the UFM1 ligase<sup>6</sup>, competes with MDM2 to bind to p53 for its stabilization. Depletion of UFL1 or DDRGK1, the critical regulator of UFMylation<sup>6,13</sup>, decreases p53 stability and in turn promotes cell growth and tumour formation in vivo. Clinically, UFL1 and DDRGK1 expression are downregulated and positively correlated with levels of p53 in a high percentage of renal cell carcinomas. Our results identify UFMylation as a crucial post-translational modification for maintenance of p53 stability and tumour-suppressive function, and point to UFMylation as a promising therapeutic target in cancer.