The REGγ Proteasome Regulates Hepatic Lipid Metabolism through Inhibition of Autophagy

Dong, Shuxian; Jia, Caifeng; Zhang, Shengping; Fan, Guangjian; Li, Yubing; Shan, Peipei; Sun, Lianhui; Xiao, Wu; Li, Lei; Zheng, Yi; Liu, Jinqin; Wei, Haibing; Hu, Chen; Zhang, Wen; Chin, Y. Eugene; Zhai, Qiwei; Qiao, Liang; Liu, Jian; Jia, Fuli; Mo, Qianxing; Edwards, Dean P.; Huang, Shixia; Chan, Lawrence; O’Malley, Bert W.; Li, Xiaotao; Wang, Chuangui

doi:10.1016/j.cmet.2013.08.012

Cited by 76 publications

(81 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Proteasome activators may recruit distinct substrates for proteasomal degradation thereby facilitating cellular recovery after protein stress. In line with this concept, both, PA28␥ and PA200, have been shown to target specific proteins for degradation via the 20S core particle: steroid receptor coactivator-3 (SRC-3), cyclin-dependent kinase inhibitors p16, p19, and p21, as well as the deacetylase SIRT1 have been identified as substrates for PA28␥-containing alternative com-plexes (6,19,20,54). Moreover, PA28␥ was shown to be involved in ubiquitin-dependent proteasomal degradation of p53 (61,62).…”

Section: Discussionmentioning

confidence: 79%

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Welk

Coux

Kleene

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The proteasome is an intracellular protease complex consisting of the 20S catalytic core and its associated regulators, including the 19S complex, PA28␣␤, PA28␥, PA200, and PI31. Inhibition of the proteasome induces autoregulatory de novo formation of 20S and 26S proteasome complexes. Formation of alternative proteasome complexes, however, has not been investigated so far. We here show that catalytic proteasome inhibition results in fast recruitment of PA28␥ and PA200 to 20S and 26S proteasomes within 2-6 h. Rapid formation of alternative proteasome complexes did not involve transcriptional activation of PA28␥ and PA200 but rather recruitment of preexisting activators to 20S and 26S proteasome complexes. Recruitment of proteasomal activators depended on the extent of active site inhibition of the proteasome with inhibition of ␤5 active sites being sufficient for inducing recruitment. Moreover, specific inhibition of 26S proteasome activity via siRNA-mediated knockdown of the 19S subunit RPN6 induced recruitment of only PA200 to 20S proteasomes, whereas PA28␥ was not mobilized. Here, formation of alternative PA200 complexes involved transcriptional activation of the activator. Alternative proteasome complexes persisted when cells had regained proteasome activity after pulse exposure to proteasome inhibitors. Knockdown of PA28␥ sensitized cells to proteasome inhibitor-mediated growth arrest. Thus, formation of alternative proteasome complexes appears to be a formerly unrecognized but integral part of the cellular response to impaired proteasome function and altered proteostasis.The proteasome, one of the main proteolytic systems of the cell, is essential for maintenance of protein homeostasis and thus of cellular functions. The proteolytic activity of this multicatalytic protease resides inside the 20S core particle, built of four stacked rings of seven ␣ and ␤ subunits with ␣ 7

show abstract

Section: Discussionmentioning

confidence: 79%

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Welk

Coux

Kleene

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…GFP-tagged REGγ deletion mutants were kindly provided by Dr. Chuangui Wang (East China Normal University, Shanghai, China). 11 Lentivirus vectors were produced by subcloning REGγ and its mutants into PLVX-ZsGreen lentivirus vector. The LPDS system was produced by subcloning firefly and Renilla CDS into pcDNA3.1 vector.…”

Section: Discussionmentioning

confidence: 99%

“…6 REGγ is involved in the regulation of aging via p53 and regulates lipid metabolism via Sirt1 degradation. 11 REGγ also affects angiogenesis by regulating PKA activity. 12 REGγ is conserved in Drosophila and one Drosophila Reg (identified as dReg) has been identified.…”

mentioning

confidence: 99%

Regulation of c-Myc protein stability by proteasome activator REGγ

Jiang

Pan

et al. 2014

Cell Death Differ

View full text Add to dashboard Cite

-Myc is a key transcriptional factor that has a prominent role in cell growth, differentiation and tumor development. Its protein levels are tightly controlled by ubiquitin-proteasome pathway and frequently deregulated in various cancers. Here, we report that the 11S proteasomal activator REGγ is a novel regulator of c-Myc abundance in cells. We showed that overexpression of wild-type REGγ, but not inactive mutants including N151Y and G250S, significantly promoted the degradation of c-Myc. Depletion of REGγ markedly increased the protein stability of c-Myc. REGγ interacts with the C-terminal region of c-Myc and regulates c-Myc protein turnover. Functionally, REGγ negatively regulates c-Myc-mediated cell proliferation. Interestingly, depletion of the Drosophila Reg homolog (dReg) in developing wings induced the upregulation of Drosophila Myc, which contributes to cell death. Collectively, these results suggest that REGγ proteasome has a conserved role in the regulation of Myc abundance in both mammalian cells and Drosophila.

show abstract

“…The REGγ gene is located in 17q21 in humans, a region with high genetic linkage to schizophrenia in Latino populations (Escamilla et al, 2009;Lewis et al, 2003) and implicated in several other CNS diseases, such as autism (Cantor et al, 2005), and bipolar disorder (Ewald et al, 2005), which share at least some symptoms with schizophrenia and schizoaffective disorders. Since the discovery of a mammalian target of REGγ, SRC3 (Steroid receptor co-activator protein; Li et al, 2006), accumulating evidence has revealed diverse functions for the ATP-and ubiquitin-independent REGγ-proteasome pathway, including regulation of cell cycle (Kobayashi et al, 2013;Li et al, 2007), angiogenesis (Liu et al, 2014), and hepatic lipid metabolism (Dong et al, 2013). REGγ is widely expressed in tissues , especially in the brain.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice

Meng

Dong

et al. 2015

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

GSK3β regulates some functions of the brain, but the mechanisms involved in the maintenance of GSK3β protein stability remain ambiguous. REGγ, an important proteasome activator for ubiquitin-independent protein degradation, has been shown to degrade certain intact proteins and is involved in the regulation of important biological processes. Here we demonstrate that REGγ promotes the degradation of GSK3β protein in vitro and in vivo. With increased GSK3β activity, REGγ knockout (REGγ − / − ) mice exhibit late-onset sensorimotor gating and cognitive deficiencies including decreased working memory, hyperlocomotion, increased stereotype, defective prepulse inhibition (PPI), and disability in nest building, at the age of 8 months or older. Inhibition of GSK3β rescued the compromised PPI phenotypes and working memory deficiency in the knockout mice. Also, we found an age-dependent decrease in the trypsin-like proteasomal activity in REGγ − / − mice brains, which may be reflective of a lack of degradation of GSK3β. Collectively, our findings reveal a novel regulatory pathway in which the REGγ-proteasome controls the steady-state level of GSK3β protein. Dysfunction in this noncanonical proteasome degradation pathway may contribute to the sensorimotor gating deficiency and cognitive disorders in aging mice.

show abstract

The REGγ Proteasome Regulates Hepatic Lipid Metabolism through Inhibition of Autophagy

Cited by 76 publications

References 45 publications

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Regulation of c-Myc protein stability by proteasome activator REGγ

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice

Contact Info

Product

Resources

About