A promiscuous α-helical motif anchors viral hijackers and substrate receptors to the CUL4–DDB1 ubiquitin ligase machinery

Li, Ti; Robert, Eva; Breugel, Pieter C. van; Strubin, Michel; Zheng, Ning

doi:10.1038/nsmb.1719

Cited by 193 publications

(295 citation statements)

References 46 publications

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“…Interestingly, in addition to binding DDB1, the SV5 V protein causes cell cycle alterations, including G 2 /M arrest, as a consequence of its association with DDB1, which is similar to our observations with UL35 (53). In addition, the hepatitis B virus and woodchuck hepatitis virus X proteins both bind to DDB1, and expression is associated with altered progression through S phase, genomic instability, and apoptosis (4,13,50,61). Another herpesvirus, murine gamma herpesvirus 68 (MHV68), also targets DDB1 through its M2 latency protein, which interacts with DDB1 as well as ATM and inhibits DNA damage-induced apoptosis (52).…”

Section: Discussionsupporting

confidence: 77%

“…There is substantial precedence for viral proteins usurping and subverting Cullin-based E3 ligase complexes (50,94). Several diverse viruses encode proteins that target DDB1-based complexes, including the paramyxovirus SV5 V protein, which binds directly to DDB1 in the absence of DCAF1and promotes the ubiquitination and degradation of STAT (71).…”

Section: Discussionmentioning

confidence: 99%

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Proteomic Profiling of the Human Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in the DNA Repair Response

Salsman

Jagannathan

Paladino

et al. 2012

J Virol

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Human cytomegalovirus infections involve the extensive modification of host cell pathways, including cell cycle control, the regulation of the DNA damage response, and averting promyelocytic leukemia (PML)-mediated antiviral responses. The UL35 gene from human cytomegalovirus is important for viral gene expression and efficient replication and encodes two proteins, UL35 and UL35a, whose mechanism of action is not well understood. Here, affinity purification coupled with mass spectrometry was used to identify previously unknown human cellular targets of UL35 and UL35a. We demonstrate that both viral proteins interact with the ubiquitin-specific protease USP7, and that UL35 expression can alter USP7 subcellular localization. In addition, UL35 (but not UL35a) was found to associate with three components of the Cul4 DCAF1 E3 ubiquitin ligase complex (DCAF1, DDB1, and DDA1) previously shown to be targeted by the HIV-1 Vpr protein. The coimmunoprecipitation and immunofluorescence microscopy of DCAF1 mutants revealed that the C-terminal region of DCAF1 is required for association with UL35 and mediates the dramatic relocalization of DCAF1 to UL35 nuclear bodies, which also contain conjugated ubiquitin. As previously reported for the Vpr-DCAF1 interaction, UL35 (but not UL35a) expression resulted in the accumulation of cells in the G 2 phase of the cell cycle, which is typical of a DNA damage response, and activated the G 2 checkpoint in a DCAF1-dependent manner. In addition, UL35 (but not UL35a) induced ␥-H2AX and 53BP1 foci, indicating the activation of DNA damage and repair responses. Therefore, the identified interactions suggest that UL35 can contribute to viral replication through the manipulation of host responses.H uman cytomegalovirus (HCMV) is a member of the betaherpesvirus subfamily and consists of an ϳ230-kbp doublestranded DNA genome encased in an icosahedral capsid, surrounded by a proteinaceous matrix (tegument) layer and a host-derived lipid bilayer containing several viral glycoproteins. HCMV can establish both lytic and latent infections in human hosts yet causes little to no adverse effect in healthy adults. However, lytic HCMV replication is associated with significant disease and sometimes death in immunocompromised hosts, typically transplant recipients, neonates, and people with AIDS (16). HCMV encodes more than 200 viral proteins, although many remain poorly or completely uncharacterized (77). The expression of specific viral proteins is temporally controlled during the three general phases of the lytic replication cycle: the immediate-early (IE), early, and late phases (73). In addition, in the pre-IE phase, tegument-derived viral proteins are delivered to the host cell preformed and therefore can act before viral gene expression occurs to manipulate cells in ways that favor lytic replication (38).Herpesvirus infections are associated with the extensive manipulation of host cell processes, including the control of the cell cycle, apoptosis, immune activation, and the DNA damage response (DDR) (...

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Proteomic Profiling of the Human Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in the DNA Repair Response

Salsman

Jagannathan

Paladino

et al. 2012

J Virol

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“…In agreement with data from previous reports, our results demonstrate that HBx interacts with DDB1 in the nucleus. This interaction has been shown to be important for transcriptional and cytotoxic activities of HBx (41,(43)(44)(45). Interestingly, we also specifically isolated the protein arginine methyltransferase PRMT1.…”

Section: Hbx Interacts With Prmt1 In Vivomentioning

confidence: 99%

Methyltransferase PRMT1 Is a Binding Partner of HBx and a Negative Regulator of Hepatitis B Virus Transcription

Benhenda

Ducroux

Rivière

et al. 2013

J Virol

105

110

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The hepatitis B virus X protein (HBx) is essential for virus replication and has been implicated in the development of liver cancer. HBx is recruited to viral and cellular promoters and activates transcription by interacting with transcription factors and coactivators. Here, we purified HBx-associated factors in nuclear extracts from HepG2 hepatoma cells and identified protein arginine methyltransferase 1 (PRMT1) as a novel HBx-interacting protein. We showed that PRMT1 overexpression reduced the transcription of hepatitis B virus (HBV), and this inhibition was dependent on the methyltransferase function of PRMT1. Conversely, depletion of PRMT1 correlated with increased HBV transcription. Using a quantitative chromatin immunoprecipitation assay, we found that PRMT1 is recruited to HBV DNA, suggesting a direct effect of PRMT1 on the regulation of HBV transcription. Finally, we showed that HBx expression inhibited PRMT1-mediated protein methylation. Downregulation of PRMT1 activity was further observed in HBV-replicating cells in an in vivo animal model. Altogether, our results support the notion that the binding of HBx to PRMT1 might benefit viral replication by relieving the inhibitory activity of PRMT1 on HBV transcription.

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“…Chronic infection of HBV causes wide-range of liver diseases including cirrhosis, hepatocellular carcinoma (HCC) that is refractory to medical treatments. HBV is the prototype member of the Hepadnaviridae family with partially double stranded genome of 3.2 kb in length [1]. It encodes seven major viral proteins: three surface antigens, two core proteins, a polymerase and a transcriptional activator (HBx).…”

Section: Introductionmentioning

confidence: 99%

HBx affects CUL4–DDB1 function in both positive and negative manners

Guo

Wang

Ren

et al. 2014

Biochemical and Biophysical Research Communications

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A promiscuous α-helical motif anchors viral hijackers and substrate receptors to the CUL4–DDB1 ubiquitin ligase machinery

Cited by 193 publications

References 46 publications

Proteomic Profiling of the Human Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in the DNA Repair Response

Proteomic Profiling of the Human Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in the DNA Repair Response

Methyltransferase PRMT1 Is a Binding Partner of HBx and a Negative Regulator of Hepatitis B Virus Transcription

HBx affects CUL4–DDB1 function in both positive and negative manners

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