ARF-mediated SUMOylation of Apak antagonizes ubiquitylation and promotes its nucleolar accumulation to inhibit 47S pre-rRNA synthesis

Ribosomes are among the most fundamental molecular machines in all cells,as they are required for protein synthesis.Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal particles.Here we show Apak,a previously identified p53 inhibitor,as a novel ribosomal stress response protein.In unstressed cells,Apak is bound to the deSUMOylase SENP1 in the nucleoplasm and targeted for proteasomal degradation by MDM2 ubiquitin ligase.Upon ribosomal stress,SENP1 dissociates fromApak and the tumor suppressor protein ARF couplesUbc9 with Apak to promote Apak SUMOylation on zinc fingers.This results in Apak protein stabilization and translocation to the nucleolus,where Apak inhibits the pre-rRNA synthesis.These findings provide a molecular mechanism whereby ARF coordinates Apak to regulate ribosome biogenesis upon cellular stress.