Termination of NF-κB activity through a gammaherpesvirus protein that assembles an EC5S ubiquitin-ligase

Rodrigues, Lénia; Filipe, Josina; Seldon, Mark P.; Fonseca, Lidia; Anrather, Josef; Soares, Miguel P.; Simas, J. Pedro

doi:10.1038/emboj.2009.74

Cited by 56 publications

(72 citation statements)

References 42 publications

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“…In addition to their essential plasmid maintenance activities, these proteins modulate numerous viral and cellular pathways (reviewed in references 37 and 61). For example, KSHV LANA binds to viral DNA and blocks the expression of Rta, the key transcriptional activator of reactivation from latency (32), induces its own expression (45), and modulates the transcription of multiple cellular genes (47). Both KSHV LANA (21) and MHV68 mLANA (19) dysregulate the activity of the tumor suppressor p53, perhaps in part as a means to promote virus growth and prevent cell death (19).…”

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“…Both KSHV LANA (21) and MHV68 mLANA (19) dysregulate the activity of the tumor suppressor p53, perhaps in part as a means to promote virus growth and prevent cell death (19). Additionally, recent reports have demonstrated the mLANA-mediated proteosomal degradation of the NF-B family member p65/RelA (47) and the activation of G 1 /S cyclin promoters via interaction with cellular bromodomain-containing BET proteins (42).…”

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confidence: 99%

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Use of a Virus-Encoded Enzymatic Marker Reveals that a Stable Fraction of Memory B Cells Expresses Latency-Associated Nuclear Antigen throughout Chronic Gammaherpesvirus Infection

Nealy

Coleman

et al. 2010

J Virol

102

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An integral feature of gammaherpesvirus infections is the ability to establish lifelong latency in B cells. During latency, the viral genome is maintained as an extrachomosomal episome, with stable maintenance in dividing cells mediated by the viral proteins Epstein-Barr nuclear antigen 1 (EBNA-1) for Epstein-Barr virus and latencyassociated nuclear antigen (LANA) for Kaposi's sarcoma-associated herpesvirus. It is believed that the expression of episome maintenance proteins is turned off in the predominant long-term latency reservoir of resting memory B cells, suggesting that chronic gammaherpesvirus infection is primarily dormant. However, the kinetics of LANA/ EBNA-1 expression in individual B-cell subsets throughout a course of infection has not been examined. The infection of mice with murine gammaherpesvirus 68 (MHV68, ␥HV68) provides a model to determine the specific cellular and molecular events that occur in vivo during lifelong gammaherpesvirus latency. In work described here, we make use of a heterologously expressed enzymatic marker to define the types of B cells that express the LANA homolog (mLANA) during chronic MHV68 infection. Our data demonstrate that mLANA is expressed in a stable fraction of B cells throughout chronic infection, with a prominent peak at 28 days. The expression of mLANA was detected in naïve follicular B cells, germinal-center B cells, and memory B cells throughout infection, with germinalcenter and memory B cells accounting for more than 80% of the mLANA-expressing cells during the maintenance phase of latency. These findings suggest that the maintenance phase of latency is an active process that involves the ongoing proliferation or reseeding of latently infected memory B cells.Gammaherpesviruses such as Epstein-Barr virus (EBV), Kaposi's sarcoma-associated virus (KSHV, HHV-8), and murine gammaherpesvirus 68 (MHV68, ␥HV68) are associated with lymphoproliferative diseases and a variety of malignancies of both epithelial and lymphoid origin. The strict species specificity exhibited by gammaherpesviruses has limited research on the human viruses primarily to in vitro studies. MHV68 is genetically colinear to the human gammaherpesviruses and exhibits many similar pathogenic features (54, 62). MHV68 is a natural pathogen of rodents (6, 9, 44), making the inoculation of mice with MHV68 a useful small-animal model to study gammaherpesvirus infection in vivo.A hallmark of gammaherpesvirus infections is the establishment of lifelong latency in B cells. During latency, the viral genome is maintained as an extrachromosomal episome, viral gene expression is highly restricted, and no new progeny virions are generated. The stable maintenance of the episome in dividing cells requires regulated plasmid DNA replication and the efficient partitioning of replicated genomes to daughter cells. These processes are mediated by critical episome maintenance protein Epstein-Barr nuclear antigen 1 (EBNA-1) for EBV and latency-associated nuclear antigen (LANA) for KSHV. EBNA-1 and LANA facilitate the re...

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Use of a Virus-Encoded Enzymatic Marker Reveals that a Stable Fraction of Memory B Cells Expresses Latency-Associated Nuclear Antigen throughout Chronic Gammaherpesvirus Infection

Nealy

Coleman

et al. 2010

J Virol

102

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“…The genetic deletion of the SOCS-box of ORF73 suppresses MuHV-4 expansion in germinal center B cells and prevents persistent MuHV-4 infection in mice. 17 This study suggests that the virus escapes host immune surveillance by using the ubiquitin-dependent proteasomal degradation pathway. In addition to degrading NFkB/p65 via the EC 2/5 S ubiquitin ligase complex, PDLIM2 alone can act as a ubiquitin ligase to induce the ubiquitination and degradation of nuclear p65 in T cells and macrophages.…”

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confidence: 90%

“…The lymphotropic gammaherpesvirus MuHV-4 (murid herpesvirus-4) ORF73 protein inhibits host NFkB transcriptional activity by inducing NFkB/p65 ubiquitination and degradation. 17 The SOCS-box motif of ORF73 acts by forming one component of the EC 5 S (ElonginC/Cullin5/SOCS) ubiquitin ligase complex. The genetic deletion of the SOCS-box of ORF73 suppresses MuHV-4 expansion in germinal center B cells and prevents persistent MuHV-4 infection in mice.…”

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confidence: 99%

Ubiquitin-mediated NFκB degradation pathway

You

Shi

et al. 2014

Cell Mol Immunol

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The nuclear factor kB (NFkB) transcription factor plays critical roles in inflammation and immunity. The dysregulation of NFkB is associated with inflammatory and autoimmune diseases and cancer. NFkB activation is negatively regulated by the ubiquitin-dependent proteasomal degradation pathway. In the present review, we discuss recent advances in our understanding of how ubiquitin ligases regulate the NFkB degradation pathway. Keywords: NFkB; ubiquitination; degradation; pathway Nuclear factor kB (NFkB) was identified approximately 20 years ago by Dr David Baltimore as a transcription factor that binds to the intronic enhancer of the kappa light chain gene (the kB site) in B cells. 1 The NFkB family is composed of several members including p50, p52, p65/RelA, c-Rel and RelB and plays a central role in cell growth, inflammation, immunity and apoptosis. NFkB activation is dependent on the stability of the inhibitor IkBa. IkBa stabilizes the NFkB complex so that after its degradation the remaining subunits translocate from the cytoplasm to the nucleus. 2 The phosphorylation of IkBa is catalyzed by IkB kinase (IKK), a complex composed of three subunits: IKKa/IKK1, IKKb/IKK2, and IKKc/NEMO. IKK1 and IKK2 are the catalytic subunits, whereas IKKc serves as a non-enzymatic regulator. [3][4][5] The IKKs/NFkB pathway is activated by extracellular stimuli such as cytokines, ultraviolet irradiation, free radicals, bacterial or viral antigens and oxidized low density lipoprotein. 3,4 In the absence of persistent upstream stimuli, NFkB transcriptional activity is terminated by the NFkB/IkBa negative feedback loop. 4 The activation of NFkB in immune or stromal cells causes a pro-inflammatory response, and persistent tissue inflammation has been linked to inflammation-associated cancer. 6 NFkB activation is negatively regulated by ubiquitin-dependent proteasomal degradation. 7-9 The ubiquitin-proteasome system comprises a ubiquitin-activating enzyme (E1), a ubiquitinconjugating enzyme (E2) and a ubiquitin ligase (E3). Ubiquitin E3 ligases play a critical role in substrate recognition and polyubiquitination by recruiting E2 ubiquitin-conjugating enzymes to specific substrates. 10 SOCS-1 (suppressor of cytokine signaling) is one of the components of the EC 2 S (Elongin BC-CUL2-SOCS-box protein) ubiquitin ligase complex that mediates JAK2 (Janus kinase 2) ubiquitination and degradation. 11,12 Similar to JAK2, NFkB/p65 is also a substrate of the EC 2 S ubiquitin ligase complex in both mice and cancer cells. 13 Pin1 increases NFkB/p65 stability and transactivation, while the loss of Pin1 leads to SOCS-1-mediated p65 ubiquitination and degradation. 13 This offers a new mechanism for NFkBmediated pathogenesis.NFkB is also activated by viral infections. In immunodeficiency virus-1-infected CD4 1 lymphocytes, NFkB activation is terminated by COMMD1 (MURR1), resulting in the inhibition of immunodeficiency virus-1 growth in unstimulated or cytokine-stimulated CD4 1 T cells. 14 This study demonstrated that COMMD1 decreases NFkB transcriptio...

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“…Examples are latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) (5,6) and murid herpesvirus 4 (MuHV-4) (7,8) (mLANA and kLANA, respectively), BZLF1 of Epstein-Barr virus (EBV) (9), Vif of human immunodeficiency virus type 1 (HIV-1) (10)(11)(12), and E4orf6/E1B55K of adenovirus (13). Several studies have shown that these viral proteins target multiple cellular substrates for polyubiquitination.…”

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confidence: 99%

Latency-Associated Nuclear Antigen E3 Ubiquitin Ligase Activity Impacts Gammaherpesvirus-Driven Germinal Center B Cell Proliferation

Cerqueira

Tan

et al. 2016

J Virol

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Viruses have evolved mechanisms to hijack components of cellular E3 ubiquitin ligases, thus modulating the ubiquitination pathway. However, the biological relevance of such mechanisms for viral pathogenesis in vivo remains largely unknown. Here, we utilized murid herpesvirus 4 (MuHV-4) infection of mice as a model system to address the role of MuHV-4 latency-associated nuclear antigen (mLANA) E3 ligase activity in gammaherpesvirus latent infection. We show that specific mutations in the mLANA SOCS box (V199A, V199A/L202A, or P203A/P206A) disrupted mLANA's ability to recruit Elongin C and Cullin 5, thereby impairing the formation of the Elongin BC/Cullin 5/SOCS (EC 5 S mLANA ) complex and mLANA's E3 ligase activity on host NF-B and Myc. Although these mutations resulted in considerably reduced mLANA binding to viral terminal repeat DNA as assessed by electrophoretic mobility shift assay (EMSA), the mutations did not disrupt mLANA's ability to mediate episome persistence. In vivo, MuHV-4 recombinant viruses bearing these mLANA SOCS box mutations exhibited a deficit in latency amplification in germinal center (GC) B cells. These findings demonstrate that the E3 ligase activity of mLANA contributes to gammaherpesvirus-driven GC B cell proliferation. Hence, pharmacological inhibition of viral E3 ligase activity through targeting SOCS box motifs is a putative strategy to control gammaherpesvirus-driven lymphoproliferation and associated disease. A s obligatory intracellular parasites, viruses have evolved mechanisms to modulate ubiquitination, which is an essential regulatory mechanism in eukaryotes, controlling a wide range of cellular pathways. Ubiquitination occurs through a threeenzyme cascade involving an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase enzyme (1). E3 ligases bind to the E2-ubiquitin intermediate and the substrate, catalyzing the transfer of ubiquitin to the substrate target lysine. Many E3 ligases have been described, such as Cullin 5-RING E3 ligases (CRL5), also known as Elongin BC/Cullin 5/SOCS (EC 5 S) E3 ligases. They are multisubunit complexes containing a scaffold protein (Cullin 5) attached to a RING finger protein (Rbx) (Cullin 5-Rbx module), an adaptor heterodimer (Elongin B/C), and a substrate recognition protein (suppressor of cytokine signaling [SOCS] box protein). The last component bridges the substrate of ubiquitination and the E3 ligase complex by interacting with Elongin B/C and Cullin 5 through a SOCS box motif (2-4). IMPORTANCE The gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause lifelong persistent infection and play causative roles in several human malignancies. Colonization of B cells is crucial for virusCertain viruses encode proteins with SOCS box motifs to hijack the components of cellular E3 ligases, thus modulating the ubiquitination pathway. Examples are latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) (5, 6) and murid he...

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Termination of NF-κB activity through a gammaherpesvirus protein that assembles an EC5S ubiquitin-ligase

Cited by 56 publications

References 42 publications

Use of a Virus-Encoded Enzymatic Marker Reveals that a Stable Fraction of Memory B Cells Expresses Latency-Associated Nuclear Antigen throughout Chronic Gammaherpesvirus Infection

Use of a Virus-Encoded Enzymatic Marker Reveals that a Stable Fraction of Memory B Cells Expresses Latency-Associated Nuclear Antigen throughout Chronic Gammaherpesvirus Infection

Ubiquitin-mediated NFκB degradation pathway

Latency-Associated Nuclear Antigen E3 Ubiquitin Ligase Activity Impacts Gammaherpesvirus-Driven Germinal Center B Cell Proliferation

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