Functional characterization of the M-type K15-encoded membrane protein of Kaposi's sarcoma-associated herpesvirus.
Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 is the causative agent of Kaposi's sarcoma, primary effusion lymphoma and the plasma-cell variant of multicentric Castleman's disease. Its alternatively spliced K15 gene encodes several membrane proteins with varying numbers of transmembrane domains. Two highly diverged alleles of the K15 gene, termed predominant (P) and minor (M), exist and share only 33 % amino acid identity with one another, but retain conserved putative src homology (SH) 2- and SH3-binding motifs. K15-M is thought to have entered the KSHV genome as the result of recombination with a related gamma(2)-herpesvirus. The more common K15-P allele has been shown to activate the mitogen-activated protein kinases Erk2 and JNK1 and the nuclear factor kappaB (NF-kappaB) pathway. To explore possible functional differences between K15-P and K15-M that might have influenced their spread in the KSHV population, here, the ability of the M form of K15 to activate these pathways was investigated. Similarly to K15-P, K15-M induces the activation of the Erk2 and JNK1 kinases, the NF-kappaB transcription factor and the expression of a similar range of cellular inflammatory genes, as assessed by gene-expression microarray studies and reporter assays. In epithelial cells, the activation of most K15-M target genes is impaired by mutagenesis of Y(490) in its SH2-binding motif Y(490)EEV, although this motif appears less important in endothelial cells. Therefore, K15-M and K15-P can trigger similar intracellular signalling pathways, despite their extensive sequence divergence.
Wang
Linding
L
Department of Virology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Brinkmann
Melanie M
MM
Department of Virology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Pietrek
Marcel
M
Department of Virology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Ottinger
Matthias
M
Department of Virology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Dittrich-Breiholz
Oliver
O
Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Kracht
Michael
M
Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Schulz
Thomas F
TF
Department of Virology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
D000483:Alleles; D019943:Amino Acid Substitution; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005814:Genes, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*
C402642:K15 protein, Human herpesvirus 8; D016328:NF-kappa B; D014764:Viral Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8