Dataset Information

PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28?.

ABSTRACT: PA28? 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? 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?, 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?. Its recruitment to proteasome-containing complexes depends on PA28? and its expression increases the association of PA28? with the 20S proteasome in cells. Further dissection of its possible roles shows that PIP30 alters PA28?-dependent activation of peptide degradation by the 20S proteasome in vitro and negatively controls in cells the presence of PA28? 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? interactions with cellular proteins, including the 20S proteasome, demonstrating that it is an important regulator of PA28? in cells and thus a new player in the control of the multiple functions of the proteasome within the nucleus.

SUBMITTER: Jonik-Nowak B

PROVIDER: S-EPMC6048556 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Jonik-Nowak Beata B Menneteau Thomas T Fesquet Didier D Baldin Véronique V Bonne-Andrea Catherine C Méchali Francisca F Fabre Bertrand B Boisguerin Prisca P de Rossi Sylvain S Henriquet Corinne C Pugnière Martine M Ducoux-Petit Manuelle M Burlet-Schiltz Odile O Lamond Angus I AI Fort Philippe P Boulon Séverine S Bousquet Marie-Pierre MP Coux Olivier O

Proceedings of the National Academy of Sciences of the United States of America 20180622 28

PA28γ 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, PA28γ 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 additiona ...[more]

PMID: 29934401

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Project description:PA28γ is a proteasome activator involved in the regulation of the cellular proliferation, differentiation and growth. In the present study, we identified and characterized a cDNA from Schistosoma mansoni exhibiting significant homology to PA28γ of diverse taxa ranging from mammals (including humans) to simple invertebrates. Designated SmPA28γ, this transcript has a 753bp predicted ORF encoding a protein of 250 amino acid residues. Alignment of SmPA28γ with multiple PA28γ orthologues revealed an average similarity of ~40% among the investigated organisms, and 90% similarity with PA28γ from Schistosoma japonicum. In addition, phylogenetic analysis demonstrated a close linkage between SmPA28γ to its sister group that contains well-characterized PA28γ sequences from Drosophila spp., as well as sharing the same branch with PA28γ from S. japonicum. Gene expression profiling of SmPA28γ using real-time quantitative PCR revealed elevated steady-state transcript levels in the eggs, miracidia and paired adult worms compared to other stages. In parallel with gene expression profiles, an affinity-purified anti-SmPA28γ antibody produced against recombinant protein exhibited strongest reactivity in Western blot analyses to endogenous SmPA28γ from miracidia, sporocysts and paired adult worms. Given its known regulatory function in other organisms, we hypothesized that the high level of SmPA28γ transcript and protein in these stages may be correlated with an important role of the PA28γ in the cellular growth and/or development of this parasite. To address this hypothesis, miracidia were transformed in vitro to sporocysts in the presence of SmPA28γ double-stranded RNAs (dsRNAs) and cultivated for 4 days, after which time steady-state transcript and protein levels, and phenotypic changes were evaluated. SmPA28γ dsRNA treatment resulted in gene and protein knockdown of ~60% and ~80%, respectively, which were correlated with a significant decrease in larval length compared to its controls. These findings are consistent with a putative role of SmPA28γ in larval growth/development of the S. mansoni.

Dataset Information

PIP30/FAM192A is a novel regulator of the nuclear proteasome activator PA28?.

Publications

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

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