PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28γ

PA28 gamma is a nuclear activator of the 20S proteasome involved in the regulation of several essential cellular processes, such as cell proliferation, apoptosis, nuclear dynamics, and cellular stress response. Unlike the 19S regulator of the proteasome, which specifically recognizes ubiquitylated proteins, PA28 gamma promotes the degradation of several substrates by the proteasome in an ATP- and ubiquitin-independent manner. However, its exact mechanisms of action are unclear and likely involve additional partners that remain to be identified. Here we report the identification of a cofactor of PA28 gamma, PIP30/FAM192A. PIP30 binds directly and specifically via its C-terminal end and in an interaction stabilized by casein kinase 2 phosphorylation to both free and 20S proteasome-associated PA28 gamma. Its recruitment to proteasome-containing complexes depends on PA28 gamma and its expression increases the association of PA28 gamma with the 20S proteasome in cells. Further dissection of its possible roles shows that PIP30 alters PA28 gamma-dependent activation of peptide degradation by the 20S proteasome in vitro and negatively controls in cells the presence of PA28 gamma in Cajal bodies by inhibition of its association with the key Cajal body component coilin. Taken together, our data show that PIP30 deeply affects PA28 gamma interactions with cellular proteins, including the 20S proteasome, demonstrating that it is an important regulator of PA28 gamma in cells and thus a new player in the control of the multiple functions of the proteasome within the nucleus.