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Fukushi, Masaya; Higuchi, Masakazu; Oie, Masayasu; Tetsuka, Takafumi; Kasolo, Francis; Ichiyama, Kouji; Yamamoto, Naoki; Katano, Harutaka; Sata, Tetsutaro; Fujii, Masahiro

doi:10.1023/a:1026391715071

Cited by 12 publications

(6 citation statements)

References 32 publications

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“…Interestingly many of these mutations appear to be in genes regulating viral DNA and innate immunity genes. Some of these TRIM and IFI family genes, which are IFN inducible genes, have already shown to be important for KSHV lytic reactivation [ 48 – 50 ]. It is likely that these mutations allow the KSHV oncovirus to express oncogenic lytic genes and that they allow for a permissive environment of inflammatory and viral tumorigenesis, which occurs in the context of DDR that may be impeded by innate immune DNA sensors.…”

Section: Discussionmentioning

confidence: 99%

High-throughput sequencing analysis of a “hit and run” cell and animal model of KSHV tumorigenesis

et al. 2020

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Kaposi's sarcoma (KS), is an AIDS-associated neoplasm caused by the KS herpesvirus (KSHV/ HHV-8). KSHV-induced sarcomagenesis is the consequence of oncogenic viral gene expression as well as host genetic and epigenetic alterations. Although KSHV is found in all KS-lesions, the percentage of KSHV-infected (LANA+) spindle-cells of the lesion is variable, suggesting the existence of KS-spindle cells that have lost KSHV and proliferate autonomously or via paracrine mechanisms. A mouse model of KSHVBac36-driven tumorigenesis allowed us to induce KSHV-episome loss before and after tumor development. Although infected cells that lose the KSHV-episome prior to tumor formation lose their tumorigenicity, explanted tumor cells that lost the KSHV-episome remained tumorigenic. This pointed to the existence of virally-induced irreversible oncogenic alterations occurring during KSHV tumorigenesis supporting the possibility of hit and run viral-sarcomagenesis. RNA-sequencing and CpG-methylation analysis were performed on KSHV-positive and KSHV-negative tumors that developed following KSHV-episome loss from explanted tumor cells. When KSHV-positive cells form KSHV-driven tumors, along with viral-gene upregulation there is a tendency for hypo-methylation in genes from oncogenic and differentiation pathways. In contrast, KSHV-negative tumors formed after KSHV-episome loss, show a tendency towards gene hyper-methylation when compared to KSHV-positive tumors. Regarding occurrence of host-mutations, we found the same set of innate-immunity related mutations undetected in KSHV-infected cells but present in all KSHV-positive tumors occurring en exactly the same position, indicating that pre-existing host mutations that provide an in vivo growth advantage are clonally-selected and contribute to KSHV-tumorigenesis. In addition, KSHV-negative tumors display de novo mutations related to cell proliferation that, together with the PDGFRAD842V and other proposed mechanism, could be responsible for

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Section: Discussionmentioning

confidence: 99%

High-throughput sequencing analysis of a “hit and run” cell and animal model of KSHV tumorigenesis

et al. 2020

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“…The novel roles being uncovered for PYHIN proteins in host defence now provide relevance for the long-established interferon-inducibility of these genes. Consistent with viral need to evade detection, several viral proteins are characterised to bind PYHIN family members [51-53]. …”

Section: Introductionmentioning

confidence: 99%

The mammalian PYHIN gene family: Phylogeny, evolution and expression

et al. 2012

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BackgroundProteins of the mammalian PYHIN (IFI200/HIN-200) family are involved in defence against infection through recognition of foreign DNA. The family member absent in melanoma 2 (AIM2) binds cytosolic DNA via its HIN domain and initiates inflammasome formation via its pyrin domain. AIM2 lies within a cluster of related genes, many of which are uncharacterised in mouse. To better understand the evolution, orthology and function of these genes, we have documented the range of PYHIN genes present in representative mammalian species, and undertaken phylogenetic and expression analyses.ResultsNo PYHIN genes are evident in non-mammals or monotremes, with a single member found in each of three marsupial genomes. Placental mammals show variable family expansions, from one gene in cow to four in human and 14 in mouse. A single HIN domain appears to have evolved in the common ancestor of marsupials and placental mammals, and duplicated to give rise to three distinct forms (HIN-A, -B and -C) in the placental mammal ancestor. Phylogenetic analyses showed that AIM2 HIN-C and pyrin domains clearly diverge from the rest of the family, and it is the only PYHIN protein with orthology across many species. Interestingly, although AIM2 is important in defence against some bacteria and viruses in mice, AIM2 is a pseudogene in cow, sheep, llama, dolphin, dog and elephant. The other 13 mouse genes have arisen by duplication and rearrangement within the lineage, which has allowed some diversification in expression patterns.ConclusionsThe role of AIM2 in forming the inflammasome is relatively well understood, but molecular interactions of other PYHIN proteins involved in defence against foreign DNA remain to be defined. The non-AIM2 PYHIN protein sequences are very distinct from AIM2, suggesting they vary in effector mechanism in response to foreign DNA, and may bind different DNA structures. The PYHIN family has highly varied gene composition between mammalian species due to lineage-specific duplication and loss, which probably indicates different adaptations for fighting infectious disease. Non-genomic DNA can indicate infection, or a mutagenic threat. We hypothesise that defence of the genome against endogenous retroelements has been an additional evolutionary driver for PYHIN proteins.

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“…The same method was used previously to isolate myeloid cell nuclear differentiation antigen (MNDA) as a LANAinteracting protein [29]. A total of 26 positive clones were obtained from this screening.…”

Section: Resultsmentioning

confidence: 99%

“…Yeast two-hybrid assay A human leukocyte cDNA library in the pACT2 prey plasmid was screened by interaction with LANA in the pGBKT7-LANA bait plasmid using the AH109 yeast strain as described previously [29]. Amino acid homology searches of cDNAs isolated by two-hybrid screening were performed with the BLAST program.…”

Section: Cell Linesmentioning

confidence: 99%

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A novel KRAB-Zinc finger protein interacts with latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus and activates transcription via terminal repeat sequences

Watanabe

Higuchi

Fukushi³

et al. 2006

Virus Genes

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Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latent infection in various cells in vitro as well as KSHV-associated tumor cells in vivo. The latency-associated nuclear antigen (LANA) of KSHV is one of a small number of genes expressed in the latent phase of KSHV infection. This antigen is crucial for establishment of the latent infection, such as replication of KSHV genomic DNA and maintenance of infection via direct interaction with terminal repeats (TRs) in the viral genome. Using a yeast two-hybrid screening method, we isolated a novel LANA-interacting protein (designated as KZLP; KRAB Zinc finger LANA interacting Protein) from a human peripheral leukocyte cDNA library. KZLP encodes a KRAB domain and 12 Kruppel-type zinc fingers. Reverse transcription polymerase chain reaction showed that KZLP was expressed ubiquitously in various cell lines including those infected with KSHV. A luciferase assay showed that KZLP could activate the KSHV open reading frame K1 promoter containing TRs in 293T cells, and that such activation required multiple TR sequences. In contrast, LANA repressed the activity of the K1 promoter through TRs, and again this repression required multiple TR units. Moreover, LANA almost completely abrogated the KZLP-mediated transcriptional activation. Our results suggest that KZLP and LANA regulate gene expression through TRs in the KSHV viral genome, including the K1 gene in latent KSHV-infected cells.

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Cited by 12 publications

References 32 publications

High-throughput sequencing analysis of a “hit and run” cell and animal model of KSHV tumorigenesis

High-throughput sequencing analysis of a “hit and run” cell and animal model of KSHV tumorigenesis

The mammalian PYHIN gene family: Phylogeny, evolution and expression

A novel KRAB-Zinc finger protein interacts with latency-associated nuclear antigen of Kaposi’s sarcoma-associated herpesvirus and activates transcription via terminal repeat sequences

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