scholarly journals Avian Metapneumovirus Subgroup C Induces Mitochondrial Antiviral Signaling Protein Degradation through the Ubiquitin-Proteasome Pathway

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1990
Author(s):  
Lei Hou ◽  
Xiaohan Hu ◽  
Jinshuo Guo ◽  
Rong Quan ◽  
Li Wei ◽  
...  
Keyword(s):  
Interaction Mechanism ◽  
Vero Cells ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Antiviral Signaling ◽  
Avian Metapneumovirus ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Mitochondrial Antiviral Signaling

The mitochondrial antiviral signaling (MAVS) protein, a critical adapter, links the upstream recognition of viral RNA to downstream antiviral signal transduction. However, the interaction mechanism between avian metapneumovirus subgroup C (aMPV/C) infection and MAVS remains unclear. Here, we confirmed that aMPV/C infection induced a reduction in MAVS expression in Vero cells in a dose-dependent manner, and active aMPV/C replication was required for MAVS decrease. We also found that the reduction in MAVS occurred at the post-translational level rather than at the transcriptional level. Different inhibitors were used to examine the effect of proteasome or autophagy on the regulation of MAVS. Treatment with a proteasome inhibitor MG132 effectively blocked MAVS degradation. Moreover, we demonstrated that MAVS mainly underwent K48-linked ubiquitination in the presence of MG132 in aMPV/C-infected cells, with amino acids 363, 462, and 501 of MAVS being pivotal sites in the formation of polyubiquitin chains. Finally, E3 ubiquitin ligases for MAVS degradation were screened and identified and RNF5 targeting MAVS at Lysine 363 and 462 was shown to involve in MAVS degradation in aMPV/C-infected Vero cells. Overall, these results reveal the molecular mechanism underlying aMPV/C infection-induced MAVS degradation by the ubiquitin-proteasome pathway.

scholarly journals Ubiquitin-dependent Degradation of p73 Is Inhibited by PML

2004 ◽  
Vol 199 (11) ◽  
pp. 1545-1557 ◽  
Author(s):  
Francesca Bernassola ◽  
Paolo Salomoni ◽  
Andrew Oberst ◽  
Charles J. Di Como ◽  
Michele Pagano ◽  
...  
Keyword(s):  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Primary Cells ◽  
Tumor Suppressor P53 ◽  
Ubiquitin Proteasome Pathway ◽  
Mitogen Activated Protein ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin–proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML–nuclear body (NB)–dependent manner. p38 mitogen-activated protein kinase–mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml−/− primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression.

scholarly journals Cks1 is degraded via the ubiquitin-proteasome pathway in a cell cycle-dependent manner

2003 ◽  
Vol 8 (11) ◽  
pp. 889-896 ◽  
Author(s):  
Takayuki Hattori ◽  
Kyoko Kitagawa ◽  
Chiharu Uchida ◽  
Toshiaki Oda ◽  
Masatoshi Kitagawa
Keyword(s):  
Cell Cycle ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner

2000 ◽  
Vol 113 (23) ◽  
pp. 4363-4371 ◽  
Author(s):  
J. Zhao ◽  
T. Tenev ◽  
L.M. Martins ◽  
J. Downward ◽  
N.R. Lemoine
Keyword(s):  
Cell Cycle ◽  
Proteasome Inhibitors ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Apoptosis Protein ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

Survivin, a human inhibitor of apoptosis protein (IAP), plays an important role in both cell cycle regulation and inhibition of apoptosis. Survivin is expressed in cells during the G(2)/M phase of the cell cycle, followed by rapid decline of both mRNA and protein levels at the G(1) phase. It has been suggested that cell cycle-dependent expression of survivin is regulated at the transcriptional level. In this study we demonstrate involvement of the ubiquitin-proteasome pathway in post-translational regulation of survivin. Survivin is a short-lived protein with a half-life of about 30 minutes and proteasome inhibitors greatly stabilise survivin in vivo. Expression of the survivin gene under the control of the CMV promoter cannot block cell cycle-dependent degradation of the protein. Proteasome inhibitors can block survivin degradation during the G(1) phase and polyubiquitinated derivatives can be detected in vivo. Mutation of critical amino acid residues within the baculovirus IAP repeat (BIR) domain or truncation of the N terminus or the C terminus sensitises survivin to proteasome degradation. Together, these results indicate that the ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner and structural changes greatly destabilise the survivin protein.

scholarly journals Degradation of Transcription Repressor ZBRK1 through the Ubiquitin-Proteasome Pathway Relieves Repression of Gadd45a upon DNA Damage

2003 ◽  
Vol 23 (20) ◽  
pp. 7305-7314 ◽  
Author(s):  
Jeanho Yun ◽  
Wen-Hwa Lee
Keyword(s):  
Dna Damage ◽  
Amino Acid ◽  
Zinc Fingers ◽  
Regulatory Region ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Krab Domain ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Acid Element

ABSTRACT Induction of gene expression in response to DNA damage is important for repairing damaged DNA for cell survival. Previously, we identified a novel zinc finger protein, ZBRK1, which contains a KRAB domain at the N terminus, eight zinc fingers at the center, and a BRCA1-binding region at the C terminus. In a BRCA1-dependent manner, ZBRK1 represses Gadd45a transcription through binding to a specific sequence in intron 3. In addition, ZBRK1-binding sequences are located at the regulatory region of many DNA damage-inducible genes, suggesting that ZBRK1 may have a role in DNA damage response. However, it is unclear how transcription repression by ZBRK1 is relieved subsequent to DNA damage. Here we report that ZBRK1 is rapidly degraded upon treatment with the DNA-damaging agents UV and methyl methanesulfonate. Specific proteasome inhibitors block DNA damage-induced degradation of ZBRK1, and the polyubiquitinated form of ZBRK1 is detectable, suggesting that the ubiquitin-proteasome pathway mediates the degradation of ZBRK1. In both BRCA1-proficient and -deficient cells, ZBRK1 is degraded with similar efficiencies independent of BRCA1 E3 ligase activity. By analysis of a series of ZBRK1 mutants, a 44-amino-acid element located between the N-terminal KRAB domain and the eight zinc fingers was found to be sufficient for the DNA damage-induced degradation of ZBRK1. Cells expressing a ZBRK1 mutant lacking the 44-amino-acid element are hypersensitive to DNA damage and are compromised for Gadd45a derepression. These results indicate that ZBRK1 is a novel target for DNA damage-induced degradation and provide a mechanistic explanation of how ZBRK1 is regulated in response to DNA damage.

scholarly journals Transferable Domain in the G1 Cyclin Cln2 Sufficient To Switch Degradation of Sic1 from the E3 Ubiquitin Ligase SCFCdc4 to SCFGrr1

2002 ◽  
Vol 22 (13) ◽  
pp. 4463-4476 ◽  
Author(s):  
Catherine Berset ◽  
Peter Griac ◽  
Rebecca Tempel ◽  
Janna La Rue ◽  
Curt Wittenberg ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Kinase Inhibitor ◽  
E3 Ubiquitin Ligase ◽  
Phosphorylation Sites ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
F Box Protein

ABSTRACT Degradation of Saccharomyces cerevisiae G1 cyclins Cln1 and Cln2 is mediated by the ubiquitin-proteasome pathway and involves the SCF E3 ubiquitin-ligase complex containing the F-box protein Grr1 (SCFGrr1). Here we identify the domain of Cln2 that confers instability and describe the signals in Cln2 that result in binding to Grr1 and rapid degradation. We demonstrate that mutants of Cln2 that lack a cluster of four Cdc28 consensus phosphorylation sites are highly stabilized and fail to interact with Grr1 in vivo. Since one of the phosphorylation sites lies within the Cln2 PEST motif, a sequence rich in proline, aspartate or glutamate, serine, and threonine residues found in many unstable proteins, we fused various Cln2 C-terminal domains containing combinations of the PEST and the phosphoacceptor motifs to stable reporter proteins. We show that fusion of the Cln2 domain to a stabilized form of the cyclin-dependent kinase inhibitor Sic1 (ΔN-Sic1), a substrate of SCFCdc4, results in degradation in a phosphorylation-dependent manner. Fusion of Cln2 degradation domains to ΔN-Sic1 switches degradation of Sic1 from SCFCdc4 to SCFGrr1. ΔN-Sic1 fused with a Cln2 domain containing the PEST motif and four phosphorylation sites binds to Grr1 and is unstable and ubiquitinated in vivo. Interestingly, the phosphoacceptor domain of Cln2 binds to Grr1 but is not ubiquitinated and is stable. In summary, we have identified a small transferable domain in Cln2 that can redirect a stabilized SCFCdc4 target for SCFGrr1-mediated degradation by the ubiquitin-proteasome pathway.

scholarly journals Ligand-dependent Degradation of Smad3 by a Ubiquitin Ligase Complex of ROC1 and Associated Proteins

2001 ◽  
Vol 12 (5) ◽  
pp. 1431-1443 ◽  
Author(s):  
Minoru Fukuchi ◽  
Takeshi Imamura ◽  
Tomoki Chiba ◽  
Takanori Ebisawa ◽  
Masahiro Kawabata ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Ring Finger ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Smads are signal mediators for the members of the transforming growth factor-β (TGF-β) superfamily. Upon phosphorylation by the TGF-β receptors, Smad3 translocates into the nucleus, recruits transcriptional coactivators and corepressors, and regulates transcription of target genes. Here, we show that Smad3 activated by TGF-β is degraded by the ubiquitin–proteasome pathway. Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCFFbw1a consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed βTrCP1) induces ubiquitination of Smad3. Recruitment of a transcriptional coactivator, p300, to nuclear Smad3 facilitates the interaction with the E3 ligase complex and triggers the degradation process of Smad3. Smad3 bound to ROC1-SCFFbw1a is then exported from the nucleus to the cytoplasm for proteasomal degradation. TGF-β/Smad3 signaling is thus irreversibly terminated by the ubiquitin–proteasome pathway.

scholarly journals Ubiquitination regulates the plasma membrane expression of renal UT-A urea transporters

2008 ◽  
Vol 295 (1) ◽  
pp. C121-C129 ◽  
Author(s):  
Gavin S. Stewart ◽  
Jennifer H. O'Brien ◽  
Craig P. Smith
Keyword(s):  
Plasma Membrane ◽  
Cellular Localization ◽  
Dependent Manner ◽  
Membrane Expression ◽  
Concentration Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Plasma Membrane Expression ◽  
Ubiquitin Proteasome ◽  
Dimethyl Urea ◽  
Proteasome Pathway

The renal UT-A urea transporters UT-A1, UT-A2, and UT-A3 are known to play an important role in the urinary concentrating mechanism. The control of the cellular localization of UT-A transporters is therefore vital to overall renal function. In the present study, we have investigated the effect of ubiquitination on UT-A plasma membrane expression in Madin-Darby canine kidney (MDCK) cell lines expressing each of the three renal UT-A transporters. Inhibition of the ubiquitin-proteasome pathway caused an increase in basal transepithelial urea flux across MDCK-rat (r)UT-A1 and MDCK-mouse (m)UT-A2 monolayers ( P < 0.01, n = 3, ANOVA) and also increased dimethyl urea-sensitive, arginine vasopressin-stimulated urea flux ( P < 0.05, n = 3, ANOVA). Inhibition of the ubiquitin-proteasome pathway also increased basolateral urea flux in MDCK-mUT-A3 monolayers ( P < 0.01, n = 4, ANOVA) in a concentration-dependent manner. These increases in urea flux corresponded to a significant increase in UT-A transporter expression in the plasma membrane ( P < 0.05, n = 3, ANOVA). Further analysis of the MDCK-mUT-A3 cell line confirmed that vasopressin specifically increased UT-A3 expression in the plasma membrane ( P < 0.05, n = 3, ANOVA). However, preliminary data suggested that vasopressin produces this effect through an alternative route to that of the ubiquitin-proteasome pathway. In conclusion, our study suggests that ubiquitination regulates the plasma membrane expression of all three major UT-A urea transporters, but that this is not the mechanism primarily used by vasopressin to produce its physiological effects.

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