The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells

Haas, Darya A.; Bala, Kiran; Büsche, Guntram; Weidner-Glunde, Magdalena; Santag, Susann; Kati, Semra; Gramolelli, Silvia; Damas, Modester; Dittrich–Breiholz, Oliver; Rückert, Jessica; Varga, Zoltán; Kéri, Gÿorgý; Schulz, Thomas F.

doi:10.1371/journal.ppat.1003737

Cited by 32 publications

(36 citation statements)

References 134 publications

(170 reference statements)

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“…To investigate the role of cGAS in the KSHV lytic replication cycle, we silenced cGAS expression using siRNA in HuAR2T.rKSHV.219, a conditionally immortalized endothelial cell line (HuAR2T) persistently infected with recombinant KSHV.219 (51). We activated the lytic replication cycle by treatment with recombinant RTA and sodium butyrate, or recombinant RTA alone, and analyzed IRF3 phosphorylation as an indicator of the activation of the cGAS-STING-IRF3 signaling pathway.…”

Section: Significancementioning

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.

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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

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Section: Significancementioning

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.

Self Cite

134

140

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“…RNA from BJAB cells, which were first selected to harbor a recombinant KSHV genome (47), was subjected to reverse transcription-quantitative PCR (RT-qPCR) as described previously (48). The cells were induced using sodium butyrate and baculovirus coding for KSHV ORF50/ RTA or the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA).…”

Section: Plasmidsmentioning

confidence: 99%

ORF57 Overcomes the Detrimental Sequence Bias of Kaposi's Sarcoma-Associated Herpesvirus Lytic Genes

Vogt¹,

Hackmann²,

Rabner³

et al. 2015

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) encodes ORF57, which enhances the expression of intronless KSHV genes on multiple posttranscriptional levels. However, it remains elusive how ORF57 recognizes viral RNAs. Here, we demonstrate that ORF57 also increases the expression of the multiple intron-containing K15 gene. The nucleotide bias of the K15 cDNA revealed an unusual high AT content. Thus, we optimized the K15 cDNA by raising the frequency of GC nucleotides, yielding an ORF57-independent version. To further prove the importance of the sequence bias of ORF57-dependent RNAs, we grouped KSHV mRNAs according to their AT content and found a correlation between AT-richness and ORF57 dependency. More importantly, latent genes, which have to be expressed in the absence of ORF57, have a low AT content and are indeed ORF57 independent. The nucleotide composition of K15 resembles that of HIV gag, which cannot be expressed unless RNA export is facilitated by the HIV Rev protein. Interestingly, ORF57 can partially rescue HIV Gag expression. Thus, the KSHV target RNAs of ORF57 and HIV gag RNA may share certain motifs based on the nucleotide bias. A bioinformatic comparison between wild-type and sequenceoptimized K15 revealed a higher density for hnRNP-binding motifs in the former. We speculate that binding of particular hnRNPs to KSHV lytic transcripts is the prerequisite for ORF57 to enhance their expression. IMPORTANCEThe mostly intronless genes of KSHV are only expressed in the presence of the viral regulator protein ORF57, but how ORF57 recognizes viral RNAs remains elusive. We focused on the multiple intron-containing KSHV gene K15 and revealed that its expression is also increased by ORF57. Moreover, sequences in the K15 cDNA mediate this enhancement. The quest for a target sequence or a response element for ORF57 in the lytic genes was not successful. Instead, we found the nucleotide bias to be the critical determinant of ORF57 dependency. Based on the fact that ORF57 has only a weak affinity for nucleic acids, we speculate that a cellular RNA-binding protein provides the sequence preference for ORF57. This study provides evidence that herpesviral RNA regulator proteins use the sequence bias of lytic genes and the resulting composition of the viral mRNP to distinguish between viral and cellular mRNAs. K aposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus that was identified in KS tissues from AIDS patients (1). It is also associated with two lymphoproliferative disorders, the primary effusion lymphoma and the plasma cell variant of multicentric Castleman's disease. KSHVassociated malignancies are rare in immunocompetent people but more common in the context of immunosuppression, especially in HIV patients or transplant recipients. The viral life cycle is divided into a latent and a lytic phase. In contrast to other herpesviruses, tumorigenesis is also a consequence of the lytic cycle (2-5).Herpesviruses replicate in the nucleus, and viral gene expression is dependent on the host ...

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“…2, knockdown of MAP4K4 affected the expression, activity or function of many factors that could act as a downstream effector or signaling mediator of MAP4K4. These factors can be grouped in several categories: kinase (MAPK/JNK) [31, 35, 39, 41]; transcription factor (NF-κB, STAT3 and HES1) [9, 31, 38, 40]; transmembrane receptor important for cell–cell communication (Notch2 and Notch3) [38]; matrix metalloproteinases (MMP, MMP-2, MMP-9, MMP-7 and MMP13) [40, 42]; inhibitor of apoptosis negative regulator of the p53 tumor suppressor (MDM2) [41] and inflammation related factor (cyclooxygenase-2 and toll-like receptors) [31, 42]. Among the above-mentioned pathways or factors, it is interesting to note that in most studies, MAP4K4 exerts its function not through canonical MAPK pathways as expected.…”

Section: Introductionmentioning

confidence: 99%

MAP4K4: an emerging therapeutic target in cancer

Gao

Liu

et al. 2016

Cell Biosci

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The serine/threonine kinase MAP4K4 is a member of the Ste20p (sterile 20 protein) family. MAP4K4 was initially discovered in 1995 as a key kinase in the mating pathway in Saccharomyces cerevisiae and was later found to be involved in many aspects of cell functions and many biological and pathological processes. The role of MAP4K4 in immunity, inflammation, metabolic and cardiovascular disease has been recognized. Information regarding MAP4K4 in cancers is extremely limited, but increasing evidence suggests that MAP4K4 also plays an important role in cancer and MAP4K4 may represent a novel actionable cancer therapeutic target. This review summarizes our current understanding of MAP4K4 regulation and MAP4K4 in cancer. MAP4K4-specific inhibitors have been recently developed. We hope that this review article would advocate more basic and preclinical research on MAP4K4 in cancer, which could ultimately provide biological and mechanistic justifications for preclinical and clinical test of MAP4K4 inhibitor in cancer patients.

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The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells

Cited by 32 publications

References 134 publications

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

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

ORF57 Overcomes the Detrimental Sequence Bias of Kaposi's Sarcoma-Associated Herpesvirus Lytic Genes

MAP4K4: an emerging therapeutic target in cancer

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