Role of Phosphatidylinositol 3-Kinase in Friend Spleen Focus-Forming Virus-Induced Erythroid Disease

Umehara, Daigo; Watanabe, Shinya; Ochi, Haruyo; Anai, Yukari; Ahmed, Nursarat; Kannagi, Mari; Hanson, Charlotte; Ruscetti, Sandra K.; Nishigaki, Kazuo

doi:10.1128/jvi.00488-10

Cited by 8 publications

(9 citation statements)

References 50 publications

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“…Immunoblotting was performed as previously described (40). Primary antibodies were goat anti-RD114 (National Cancer Institute [NCI], Frederick, MD), goat anti-FeLV gp70 (NCI), and mouse anti-beta actin (Santa Cruz Biotechnology, Santa Cruz, CA).…”

Section: Methodsmentioning

confidence: 99%

Infectious Endogenous Retroviruses in Cats and Emergence of Recombinant Viruses

Anai

Ochi

Watanabe

et al. 2012

J Virol

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189

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bEndogenous retroviruses (ERVs) comprise a significant percentage of the mammalian genome, and it is poorly understood whether they will remain as inactive genomes or emerge as infectious retroviruses. Although several types of ERVs are present in domestic cats, infectious ERVs have not been demonstrated. Here, we report a previously uncharacterized class of endogenous gammaretroviruses, termed ERV-DCs, that is present and hereditary in the domestic cat genome. We have characterized a subset of ERV-DC proviral clones, which are numbered according to their genomic insertions. One of these, ERV-DC10, located in the q12-q21 region on chromosome C1, is an infectious gammaretrovirus capable of infecting a broad range of cells, including human. Our studies indicate that ERV-DC10 entered the genome of domestic cats in the recent past and appeared to translocate to or reintegrate at a distinct locus as infectious ERV-DC18. Insertional polymorphism analysis revealed that 92 of 244 domestic cats had ERV-DC10 on a homozygous or heterozygous locus. ERV-DC-like sequences were found in primate and rodent genomes, suggesting that these ERVs, and recombinant viruses such as RD-114 and BaEV, originated from an ancestor of ERV-DC. We also found that a novel recombinant virus, feline leukemia virus subgroup D (FeLV-D), was generated by ERV-DC env transduction into feline leukemia virus in domestic cats. Our results indicate that ERV-DCs behave as donors and/or acceptors in the generation of infectious, recombinant viruses. The presence of such infectious endogenous retroviruses, which could be harmful or beneficial to the host, may affect veterinary medicine and public health.

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Section: Methodsmentioning

confidence: 99%

Infectious Endogenous Retroviruses in Cats and Emergence of Recombinant Viruses

Anai

Ochi

Watanabe

et al. 2012

J Virol

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189

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“…Immunoblotting. Immunoblotting was performed as previously described (67). The primary antibodies used in these assays were goat polyclonal anti-FeLV SU (gp70; National Cancer Institute [NCI], Frederick, MD, USA), mouse monoclonal anti-FeLV SU (gp70; antibody C11D8; Custom Monoclonals…”

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confidence: 99%

Tracking the Fate of Endogenous Retrovirus Segregation in Wild and Domestic Cats

Ngo

Arnal

Sumi

et al. 2019

J Virol

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Endogenous retroviruses (ERVs) of domestic cats (ERV-DCs) are one of the youngest feline ERV groups in domestic cats (Felis silvestris catus); some members are replication competent (ERV-DC10, ERV-DC18, and ERV-DC14), produce the antiretroviral soluble factor Refrex-1 (ERV-DC7 and ERV-DC16), or can generate recombinant feline leukemia virus (FeLV). Here, we investigated ERV-DC in European wildcats (Felis silvestris silvestris) and detected four loci: ERV-DC6, ERV-DC7, ERV-DC14, and ERV-DC16. ERV-DC14 was detected at a high frequency in European wildcats; however, it was replication defective due to a single G → A nucleotide substitution, resulting in an E148K substitution in the ERV-DC14 envelope (Env). This mutation results in a cleavage-defective Env that is not incorporated into viral particles. Introduction of the same mutation into feline and murine infectious gammaretroviruses resulted in a similar Env dysfunction. Interestingly, the same mutation was found in an FeLV isolate from naturally occurring thymic lymphoma and a mouse ERV, suggesting a common mechanism of virus inactivation. Refrex-1 was present in European wildcats; however, ERV-DC16, but not ERV-DC7, was unfixed in European wildcats. Thus, Refrex-1 has had an antiviral role throughout the evolution of the genus Felis, predating cat exposure to feline retroviruses. ERV-DC sequence diversity was present across wild and domestic cats but was locus dependent. In conclusion, ERVs have evolved species-specific phenotypes through the interplay between ERVs and their hosts. The mechanism of viral inactivation may be similar irrespective of the evolutionary history of retroviruses. The tracking of ancestral retroviruses can shed light on their roles in pathogenesis and host-virus evolution. IMPORTANCE Domestic cats (Felis silvestris catus) were domesticated from wildcats approximately 9,000 years ago via close interaction between humans and cats. During cat evolution, various exogenous retroviruses infected different cat lineages and generated numerous ERVs in the host genome, some of which remain replication competent. Here, we detected several ERV-DC loci in Felis silvestris silvestris. Notably, a species-specific single nucleotide polymorphism in the ERV-DC14 env gene, which results in a replication-defective product, is highly prevalent in European wildcats, unlike the replication-competent ERV-DC14 that is commonly present in domestic cats. The presence of the same lethal mutation in the env genes of both FeLV and murine ERV provides a common mechanism shared by endogenous and exogenous retroviruses by which ERVs can be inactivated after endogenization. The antiviral role of Refrex-1 predates cat exposure to feline retroviruses. The existence of two ERV-DC14 phenotypes provides a unique model for understanding both ERV fate and cat domestication.

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“…Importance of sf-Stk residues 16-20 for fibroblast transformation in conjunction with SFFV-P and SFFV-A Based on the results shown in Figure 1, we next investigated amino acid positions [16][17][18][19][20] (Figs. 2c and 2d).…”

Section: Resultsmentioning

confidence: 99%

“…These include the JAK/STAT, Ras/Raf/mitogen-activated protein kinase, Jun N-terminal kinase, protein kinase C and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. [9][10][11][12][13][14][15][16][17][18] SFFV gp55 is thought to activate these pathways by interacting with either the EpoR or the sf-Stk. [19][20][21][22] sf-Stk interacts with SFFV Env gp55 in hematopoietic cells that express the EpoR and that this interaction induces sf-Stk activation.…”

mentioning

confidence: 99%

Role of N‐terminal sequences of the tyrosine kinase sf‐Stk in transformation of rodent fibroblasts by variants of Friend spleen focus‐forming virus

Umehara

Kawamura

Odahara

et al. 2011

Intl Journal of Cancer

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Infection of erythroid cells by Friend spleen focus-forming virus (SFFV) leads to acute erythroid hyperplasia in mice, due to expression of its unique envelope glycoprotein, gp55. Erythroid cells expressing SFFV gp55 proliferate in the absence of their normal regulator, erythropoietin, because of the interaction among the viral envelope protein, the erythropoietin receptor, and a short form of the receptor tyrosine kinase Stk (sf-Stk). This leads to constitutive activation of several signal transduction pathways. Our previous studies showed that sf-Stk interacts with SFFV gp55, forming disulfide-linked complexes. This covalent interaction, along with other noncovalent interactions with SFFV-gp55, results in constitutive tyrosine phosphorylation of sf-Stk and rodent fibroblast transformation. Here, we determined the precise amino acid region within sf-Stk that contributes to fibroblast transformation by the polycythemia-inducing (SFFV-P) and the anemia-inducing (SFFV-A) strains of SFFV. Sf-Stk deletion mutants showed different transforming abilities in fibroblasts infected with SFFV-P and SFFV-A, although the N-terminal extracellular domain of sf-Stk was essential for fibroblast transformation by both viruses. Point mutations of sf-Stk indicated that cysteine 19 was critical for fibroblast transformation by SFFV-P, although all four cysteines (8, 19, 37 and 42) appeared to be important for fibroblast transformation by both SFFV-P and SFFV-A. Mutation of sf-Stk cysteine 19 abolished its ability to form dimers with SFFV-P and SFFV-A gp55. These results suggest that the interaction between sf-Stk and the envelope proteins of the polycythemia-and anemia-inducing variants of SFFV is architecturally different.The Friend spleen focus-forming virus (SFFV) is a highly pathogenic retrovirus that induces rapid erythroblastosis in susceptible strains of mice.1 Friend SFFV is a replication-defective virus with deletions in its env gene that give rise to a unique glycoprotein, SFFV gp55. This unique glycoprotein confers pathogenicity on the virus; a vector encoding SFFV gp55 alone is sufficient to induce erythroblastosis in susceptible strains of mice.2 The Fv-2 gene encodes one of the key susceptibility factors for SFFV-induced erythroid disease 3,4 : the receptor tyrosine kinase Stk/RON, a member of the Met family of receptor tyrosine kinases. 5,6 Susceptibility to SFFVinduced disease is associated with expression of a short form of Stk, termed sf-Stk, which is transcribed from an internal promoter within the Stk gene of susceptible mice (Fv-2 ss ) but not in resistant mice (Fv-2 rr ), 4 and is abundantly expressed in erythroid cells.5 Infection of Fv-2 ss erythroid cells with the polycythemia-inducing strain of SFFV (SFFV-P) induces erythropoietin (Epo)-independent proliferation and differentiation, whereas erythroid cells infected with the anemiainducing strain of SFFV (SFFV-A) proliferate in the absence of Epo but still require Epo for differentiation.7 A number of signaling pathways, normally activated in erythroid cells...

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Role of Phosphatidylinositol 3-Kinase in Friend Spleen Focus-Forming Virus-Induced Erythroid Disease

Cited by 8 publications

References 50 publications

Infectious Endogenous Retroviruses in Cats and Emergence of Recombinant Viruses

Infectious Endogenous Retroviruses in Cats and Emergence of Recombinant Viruses

Tracking the Fate of Endogenous Retrovirus Segregation in Wild and Domestic Cats

Role of N‐terminal sequences of the tyrosine kinase sf‐Stk in transformation of rodent fibroblasts by variants of Friend spleen focus‐forming virus

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