Identification and Characterization of a DrosophilaNuclear Proteasome Regulator

Masson, Patrick; Andersson, Oskar; Petersen, Ulla‐Maja; Young, Patrick

doi:10.1074/jbc.m007379200

Cited by 52 publications

(44 citation statements)

References 45 publications

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“…on May 12, 2018 by guest http://ec.asm.org/ been shown to contain a conserved nuclear localization signal (NLS) (17). For the homolog-specific region, the Dictyostelium REG sequence shows by far the shortest loop sequence of all identified REG sequences: the loop region is almost absent except for a small region that shows strong similarity to the proposed REG␥ NLS.…”

Section: Resultsmentioning

confidence: 99%

Characterization of a REG/PA28 Proteasome Activator Homolog in Dictyostelium discoideum Indicates that the Ubiquitin- and ATP-Independent REGγ Proteasome Is an Ancient Nuclear Protease

et al. 2009

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The nuclear proteasome activator REG␥/PA28␥ is an ATP-and ubiquitin-independent activator of the 20S proteasome and has been proposed to degrade and thereby regulate both a key human oncogene, encoding the coactivator SRC-3/AIB1, and the cyclin-dependent kinase inhibitor p21 (Waf/Cip1). We report the identification and characterization of a PA28/REG homolog in Dictyostelium. Association of a recombinant Dictyostelium REG with the purified Dictyostelium 20S proteasome led to the preferential stimulation of the trypsin-like proteasome peptidase activity. Immunolocalization studies demonstrated that the proteasome activator is localized to the nucleus and is present in growing as well as starving Dictyostelium cells. Our results indicate that the Dictyostelium PA28/REG activator can stimulate both the trypsin-like and chymotrypsin-like activities of the 20S proteasome and supports the idea that the REG␥-20S proteasome represents an early unique nuclear degradation pathway for eukaryotic cells.

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Section: Resultsmentioning

confidence: 99%

Characterization of a REG/PA28 Proteasome Activator Homolog in Dictyostelium discoideum Indicates that the Ubiquitin- and ATP-Independent REGγ Proteasome Is an Ancient Nuclear Protease

et al. 2009

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“…PA28␥ is well conserved from invertebrates to vertebrates, and amino acid sequences of human and murine PA28␥s are identical (19). The homologous proteins, PA28␣ and PA28␤, form a heteroheptamer in the cytoplasm, and they activate chymotrypsin-like peptidase activity of the 20S proteasome, whereas PA28␥ forms a homoheptamer in the nucleus, and it enhances trypsin-like peptidase activity of 20S proteasome (20).…”

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confidence: 99%

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Moriishi

Mochizuki

Moriya

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

191

196

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Hepatitis C virus (HCV) is a major cause of chronic liver disease that frequently leads to steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCV core protein is not only a component of viral particles but also a multifunctional protein because liver steatosis and HCC are developed in HCV core gene-transgenic (CoreTg) mice. Proteasome activator PA28␥/REG␥ regulates host and viral proteins such as nuclear hormone receptors and HCV core protein. Here we show that a knockout of the PA28␥ gene induces the accumulation of HCV core protein in the nucleus of hepatocytes of CoreTg mice and disrupts development of both hepatic steatosis and HCC. Furthermore, the genes related to fatty acid biosynthesis and srebp-1c promoter activity were up-regulated by HCV core protein in the cell line and the mouse liver in a PA28␥-dependent manner. Heterodimer composed of liver X receptor ␣ (LXR␣) and retinoid X receptor ␣ (RXR␣) is known to up-regulate srebp-1c promoter activity. Our data also show that HCV core protein enhances the binding of LXR␣/RXR␣ to LXR-response element in the presence but not the absence of PA28␥. These findings suggest that PA28␥ plays a crucial role in the development of liver pathology induced by HCV infection.fatty acid ͉ proteasome ͉ sterol regulatory element-binding protein (SREBP) ͉ RXR␣ ͉ LXR␣ H epatitis C virus (HCV) belongs to the Flaviviridae family, and it possesses a positive, single-stranded RNA genome that encodes a single polyprotein composed of Ϸ3,000 aa. The HCV polyprotein is processed by host and viral proteases, resulting in 10 viral proteins. Viral structural proteins, including the capsid (core) protein and two envelope proteins, are located in the N-terminal one-third of the polyprotein, followed by nonstructural proteins.HCV infects Ͼ170 million individuals worldwide, and then it causes liver disease, including hepatic steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC) (1). The prevalence of fatty infiltration in the livers of chronic hepatitis C patients has been reported to average Ϸ50% (2, 3), which is higher than the percentage in patients infected with hepatitis B virus and other liver diseases. However, the precise functions of HCV proteins in the development of fatty liver remain unknown because of the lack of a system sufficient to investigate the pathogenesis of HCV. HCV core protein expression has been shown to induce lipid droplets in cell lines and hepatic steatosis and HCC in transgenic mice (4-6). These reports suggest that HCV core protein plays an important role in the development of various types of liver failure, including steatosis and HCC.Recent reports suggest that lipid biosynthesis affects HCV replication (7-9). Involvement of a geranylgeranylated host protein, FBL2, in HCV replication through the interaction with NS5A suggests that the cholesterol biosynthesis pathway is also important for HCV replication (9). Increases in saturated and monounsaturated fatty acids enhance HCV RNA replication, whereas increases in polyunsaturat...

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“…It is well known that PA28␥ enhances the latent proteasome activity of the 20S proteasome and is predominantly localized in the nucleus (48,62). PA28␥ is conserved across the animal kingdom from invertebrates to vertebrates (34,47), although the biological significance of PA28␥ is largely unknown. Here, we demonstrate through several lines of evidence that PA28␥ specifically interacts with the HCV core protein and remains in the nucleus, consequently regulating its stability.…”

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confidence: 99%

Proteasome Activator PA28γ-Dependent Nuclear Retention and Degradation of Hepatitis C Virus Core Protein

Moriishi

Okabayashi

Nakai

et al. 2003

J Virol

143

145

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Hepatitis C virus (HCV) core protein plays an important role in the formation of the viral nucleocapsid and a regulatory protein involved in hepatocarcinogenesis. In this study, we have identified proteasome activator PA28␥ (11S regulator ␥) as an HCV core binding protein by using yeast two-hybrid system. This interaction was demonstrated not only in cell culture but also in the livers of HCV core transgenic mice. These findings are extended to human HCV infection by the observation of this interaction in liver specimens from a patient with chronic HCV infection. Neither the interaction of HCV core protein with other PA28 subtypes nor that of PA28␥ with other Flavivirus core proteins was detected. Deletion of the PA28␥-binding region from the HCV core protein or knockout of the PA28␥ gene led to the export of the HCV core protein from the nucleus to the cytoplasm. Overexpression of PA28␥ enhanced the proteolysis of the HCV core protein. Thus, the nuclear retention and stability of the HCV core protein is regulated via a PA28␥-dependent pathway through which HCV pathogenesis may be exerted.Hepatitis C virus (HCV) is the causative agent in most cases of acute and chronic non-A, non-B hepatitis (16, 51). Over 50% of patients with acute infection evolve into a chronic carrier state (26), and persistent infection frequently results in chronic hepatitis. Chronic HCV infection may lead to the development of cirrhosis and eventually hepatocellular carcinoma (21, 51). HCV belongs to the Flaviviridae family, a family that also includes Japanese encephalitis virus (JEV) and Dengue fever virus (DEN), and possesses a viral genome consisting of a single positive-strand RNA of approximately 9.6 kb and encoding approximately 3,000 amino acids in a single polypeptide (9, 58). HCV proteins are produced as a single polypeptide that is posttranslationally cleaved by host cellular peptidases and viral proteases to yield at least 10 viral proteins (7,10,12,54).A comparison of the genome structure of HCV with other flaviviruses, as well as the observation of a specific interaction of viral sense RNA with HCV core protein in cells (53, 68), suggests that the HCV core protein forms the nucleocapsid with viral genome RNA. An HCV core protein consisting of the N-terminal 191 amino acids is generated by protein cleavage by host signal peptidase(s) (37, 52). The HCV core protein is further processed into a mature core protein lacking its C-terminal hydrophobic region by either an unknown host protease (52, 65) or by a signal peptide peptidase (36). The matured core protein is retained on the endoplasmic reticulum (ER) either by an interaction with immature core protein on the ER membrane (29) or via E1 envelope protein (32). The C-terminal hydrophobic region between amino acids 174 and 191 is essential for HCV core protein anchoring on the ER membrane and for the signal sequence of E1 protein to translocate into the ER lumen. Core proteins truncated at the C termini are mainly localized in the nucleus and, to lesser extent, in the cytoplasm...

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Identification and Characterization of a DrosophilaNuclear Proteasome Regulator

Cited by 52 publications

References 45 publications

Characterization of a REG/PA28 Proteasome Activator Homolog in Dictyostelium discoideum Indicates that the Ubiquitin- and ATP-Independent REGγ Proteasome Is an Ancient Nuclear Protease

Characterization of a REG/PA28 Proteasome Activator Homolog in Dictyostelium discoideum Indicates that the Ubiquitin- and ATP-Independent REGγ Proteasome Is an Ancient Nuclear Protease

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Proteasome Activator PA28γ-Dependent Nuclear Retention and Degradation of Hepatitis C Virus Core Protein

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