A Role for Host Activation-Induced Cytidine Deaminase in Innate Immune Defense against KSHV

Bekerman, Elena; Jeon, Diana; Ardolino, Michele; Coscoy, Laurent

doi:10.1371/journal.ppat.1003748

Cited by 43 publications

(52 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, HSV-1 reactivation was measured post-explant from trigeminal ganglia: a tissue composed of terminally differentiated adult neurons with low levels of host UNG (18,36). Reactivation is also reduced in human gammaherpesvirus latency cell systems lacking the EBV viral UNG (BKRF3) alone or in the absence of both the vUNG and the host UNG (13,18,(37)(38)(39). Interestingly, Su et al (13) recently reported that host UNG2 levels decrease as EBV reactivation proceeds, indicating that the viral UNG is needed to promote replication under conditions of low host UNG levels (13).…”

Section: Discussionmentioning

confidence: 99%

“…This implicates a possible role for the vUNG in impacting B cell processes critical for gammaherpesvirus pathogenesis. Alternatively, given that gammaherpesviruses target B cells that undergo isotype-class switching and, in some reports, upregulate the B cell specific host cytidine deaminase, AID (39,43), it is possible that mutagenic effects of AID may exert a selective pressure that must be countered by the vUNG. Indeed, overexpression of AID impairs reactivation in KSHV-positive latent BCBL cell lines, and this defect is exacerbated with depletion of host UNG2 (39).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Absence of the Uracil DNA Glycosylase of Murine Gammaherpesvirus 68 Impairs Replication and Delays the Establishment of Latency In Vivo

Minkah

Macaluso

Oldenburg

et al. 2015

J Virol

View full text Add to dashboard Cite

Uracil DNA glycosylases (UNG) are highly conserved proteins that preserve DNA fidelity by catalyzing the removal of mutagenic uracils. All herpesviruses encode a viral UNG (vUNG), and yet the role of the vUNG in a pathogenic course of gammaherpesvirus infection is not known. First, we demonstrated that the vUNG of murine gammaherpesvirus 68 (MHV68) retains the enzymatic function of host UNG in an in vitro class switch recombination assay. Next, we generated a recombinant MHV68 with a stop codon in ORF46/UNG (⌬UNG) that led to loss of UNG activity in infected cells and a replication defect in primary fibroblasts. Acute replication of MHV68⌬UNG in the lungs of infected mice was reduced 100-fold and was accompanied by a substantial delay in the establishment of splenic latency. Latency was largely, yet not fully, restored by an increase in virus inoculum or by altering the route of infection. MHV68 reactivation from latent splenocytes was not altered in the absence of the vUNG. A survey of host UNG activity in cells and tissues targeted by MHV68 indicated that the lung tissue has a lower level of enzymatic UNG activity than the spleen. Taken together, these results indicate that the vUNG plays a critical role in the replication of MHV68 in tissues with limited host UNG activity and this vUNG-dependent expansion, in turn, influences the kinetics of latency establishment in distal reservoirs. IMPORTANCEHerpesviruses establish chronic lifelong infections using a strategy of replicative expansion, dissemination to latent reservoirs, and subsequent reactivation for transmission and spread. We examined the role of the viral uracil DNA glycosylase, a protein conserved among all herpesviruses, in replication and latency of murine gammaherpesvirus 68. We report that the viral UNG of this murine pathogen retains catalytic activity and influences replication in culture. The viral UNG was impaired for productive replication in the lung. This defect in expansion at the initial site of acute replication was associated with a substantial delay of latency establishment in the spleen. The levels of host UNG were substantially lower in the lung compared to the spleen, suggesting that herpesviruses encode a viral UNG to compensate for reduced host enzyme levels in some cell types and tissues. These data suggest that intervention at the site of initial replicative expansion can delay the establishment of latency, a hallmark of chronic herpesvirus infection.A ll herpesvirus genomes encode a homolog of the host uracil DNA glycosylase. If not repaired, uracil misincorporation during DNA replication (1, 2) or conversion upon cytosine deamination (2, 3) will lead to a C:G-to-T:A transition mutation that may have severe consequences for genomic integrity (1). In the host, the recognition and removal of uracils is mediated by members of the uracil DNA glycosylase (UDG) superfamily. UNG2 is the predominant nuclear enzyme responsible for initiating repair (2-6). The role of a seemingly redundant herpesvirus UNG in viral replication is ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Absence of the Uracil DNA Glycosylase of Murine Gammaherpesvirus 68 Impairs Replication and Delays the Establishment of Latency In Vivo

Minkah

Macaluso

Oldenburg

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…The KSHV-infected cell presents antigenic peptides from the virus in complex with MHC class I to cytotoxic T lymphocytes (CTLs) (64)(65)(66). Additionally, KSHV-infected B cells stimulate activation-induced cytidine deaminase (AID) expression and are targeted for elimination by NK cells through upregulation of NKG2D ligands (67). KSHV also encodes genes that inhibit these immune responses.…”

Section: Latent Kshv Infection and Reactivationmentioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

182

152

View full text Add to dashboard Cite

“…Meanwhile, host restriction factors inhibit KSHV infection by activating immune responses. KSHV infection of human primary naïve B cells induces rapid activation-induced cytidine deaminase (AID) expression, which plays a role in the innate immune defense against KSHV (29).…”

mentioning

confidence: 99%

Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

Zhang

Chan

Samarina

et al. 2016

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

136

140

View full text Add to dashboard Cite

The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGASmediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle.KSHV | cytoplasmic LANA | cyclic GMP-AMP synthase

show abstract

A Role for Host Activation-Induced Cytidine Deaminase in Innate Immune Defense against KSHV

Cited by 43 publications

References 85 publications

Absence of the Uracil DNA Glycosylase of Murine Gammaherpesvirus 68 Impairs Replication and Delays the Establishment of Latency In Vivo

Absence of the Uracil DNA Glycosylase of Murine Gammaherpesvirus 68 Impairs Replication and Delays the Establishment of Latency In Vivo

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

Contact Info

Product

Resources

About