Autophagic degradation of the inhibitory p53 isoform Delta 133p53 alpha as a regulatory mechanism for p53-mediated senescence

作者：Horikawa Izumi; Fujita Kaori; Jenkins Lisa M Miller; Hiyoshi Yukiharu; Mondal Abdul M; Vojtesek Borivoj; Lane David P; Appella Ettore; Harris Curtis C^*

来源：Nature Communications, 2014, 5(1): 4706.

DOI：10.1038/ncomms5706

Delta 133p53 alpha, a p53 isoform that can inhibit full-length p53, is downregulated at replicative senescence in a manner independent of mRNA regulation and proteasome-mediated degradation. Here we demonstrate that, unlike full-length p53, Delta 133p53 alpha is degraded by autophagy during replicative senescence. Pharmacological inhibition of autophagy restores Delta 133p53 alpha expression levels in replicatively senescent fibroblasts, without affecting full-length p53. The siRNA-mediated knockdown of pro-autophagic proteins (ATG5, ATG7 and Beclin-1) also restores Delta 133p53 alpha expression. The chaperone-associated E3 ubiquitin ligase STUB1, which is known to regulate autophagy, interacts with Delta 133p53 alpha and is downregulated at replicative senescence. The siRNA knockdown of STUB1 in proliferating, early-passage fibroblasts induces the autophagic degradation of Delta 133p53 alpha and thereby induces senescence. Upon replicative senescence or STUB1 knockdown, Delta 133p53 alpha is recruited to autophagosomes, consistent with its autophagic degradation. This study reveals that STUB1 is an endogenous regulator of Delta 133p53 alpha degradation and senescence, and identifies a p53 isoform-specific protein turnover mechanism that orchestrates p53-mediated senescence.

• 出版日期2014-8