The Ubiquitination of arrestin3 within the Nucleus Triggers the Nuclear Export of Mdm2, Which, in Turn, Mediates the Ubiquitination of GRK2 in the Cytosol

GRK2 and arrestin3, key players in the functional regulation of G protein-coupled receptors (GPCRs), are ubiquitinated by Mdm2, a nuclear protein. The agonist-induced increase in arrestin3 ubiquitination occurs in the nucleus, underscoring the crucial role of its nuclear translocation in this process. Agonist-induced increase in the ubiquitination of arrestin3 occurs in the nucleus, highlighting the pivotal role of its nuclear translocation in this process. In contrast, GRK2 cannot translocate into the nucleus, thus facilitating the cytosolic translocation of nuclear Mdm2 is required to ubiquitinate GRK2 in the cytosol. Among the cellular components and processes explored, arrestin, Gβγ, clathrin, and receptor phosphorylation were required for the nuclear import of arrestin3, ubiquitination of arrestin3 in the nucleus, nuclear export of Mdm2, and the ubiquitination of GRK2 in the cytosol. In conclusion, our findings demonstrate that agonist-induced ubiquitination of arrestin3 in the nucleus is interconnected to the cytosolic GRK2 ubiquitination.