REGγ proteasome activator is involved in the maintenance of chromosomal stability

Abstract

REGγ is a member of the 11S regulatory particle that activates the 20S proteasome. Studies in REGγ deficient mice indicated an additional role for this protein in cell cycle regulation and proliferation control. In this paper we demonstrate that REGγ protein is equally expressed throughout the cell cycle, but undergoes a distinctive subcellular localization at mitosis. Thus, while in interphase cells REGγ is nuclear, in telophase cells it localizes on chromosomes, suggesting a role in mitotic progression. Furthermore, we found that REGγ overexpression weakens the mitotic arrest induced by spindle damage, allowing premature exit from mitosis, whereas REGγ depletion has the opposite effect, thus reflecting a new REGγ function, unrelated to its role as proteasome activator. Additionally, we found that primary cells from REGγ -/-mice and human fibroblasts with depleted expression of REGγ or overexpressing a dominant negative mutant unable to activate the 20S proteasome, demonstrated a marked aneuploidy (chromosomal gains and losses), supernumerary centrosomes and multipolar spindles. These findings thus underscore a previously uncharacterized function of REGγ in centrosome and chromosomal stability maintenance.

The proteasome: molecular machinery and pathophysiological roles

“…It is worth noting that PA28 γ is localized in the nucleus in interphase cells and on chromosomes in telophase cells, suggesting a role in mitotic progression. This conclusion is supported by the marked aneuploidy (chromosomal gain and loss), supernumerary centrosomes, and multipolar spindles observed in the fi broblasts of PA28 γ -defi cient mice (Zannini et al , 2008 ). These fi ndings underscore a previously uncharacterized function of PA28 γ in centrosomes and chromosomal stability.…”

REGγ, a proteasome activator and beyond?

“…This REGg redistribution and interaction with MEKK3 may be significant in the context of mitosis progression and exit [38]. Interestingly, it was reported that REGg undergoes an intranuclear redistribution at mitosis [43]. During telophase, REGg was found to be localized on the chromosomes [43].…”

“…Decreased levels of p53 allow cells to pass through the G1/S checkpoint during cell cycle progression. Other studies have shown that REGg may play a key role in chromosomal stability during mitosis [43] and in the organization of nuclear speckles [44]. Furthermore, there was a report implicating a potential function of REGg in regulating the activity of G protein-coupled receptors through binding with the C-terminus of thromboxane A 2 receptor [45].…”

“…Interestingly, it was reported that REGg undergoes an intranuclear redistribution at mitosis [43]. During telophase, REGg was found to be localized on the chromosomes [43]. Overexpression of REGg has been shown to weaken spindle damage-induced mitotic arrest and allow cells to escape, leading to a premature exit of mitosis [43].…”

Proteasome Activator REGγ Enhances Coxsackieviral Infection by Facilitating p53 Degradation

“…Although sumoylation has most often been implicated in promoting nuclear import (11), there is evidence that sumoylation can also serve as a signal for cytoplasmic translocation of some protein substrates, such as TEL (39), Smad3 (13), Med (23), MEK1 (34), and heterogeneous nuclear ribonucleoproteins M and C (37). REG␥ has been suggested to be a potential nucleocytoplasmic shuttling protein (42). However, the mechanisms regulating REG␥ nuclear import/export have not yet been fully characterized.…”