Complement regulation by Kaposi's sarcoma-associated herpesvirus ORF4 protein.
Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with three types of human tumor: Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. The virus encodes a number of proteins that participate in disrupting the immune response, one of which was predicted by sequence analysis to be encoded by open reading frame 4 (ORF4). The predicted ORF4 protein shares homology with cellular proteins referred to as regulators of complement activation. In the present study, the transcription profile of the ORF4 gene was characterized, revealing that it encodes at least three transcripts, by alternative splicing mechanisms, and three protein isoforms. Functional studies revealed that each ORF4 protein isoform inhibits complement and retains a C-terminal transmembrane domain. Consistent with the complement-regulating activity, we propose to name the proteins encoded by the ORF4 gene collectively as KSHV complement control protein (KCP). KSHV ORF4 is the most complex alternatively spliced gene encoding a viral complement regulator described to date. KCP inhibits the complement component of the innate immune response, thereby possibly contributing to the in vivo persistence and pathogenesis of this virus.
Spiller
O Brad
OB
Department of Medical Biochemistry, University of Wales College of Medicine, Cardiff CF14 4XX, United Kingdom.
Robinson
Mairi
M
O'Donnell
Elizabeth
E
Milligan
Steven
S
Morgan
B Paul
BP
Davison
Andrew J
AJ
Blackbourn
David J
DJ
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D018958:CD55 Antigens / Q000737:chemistry / Q000502:physiology; D016466:CHO Cells; D003001:Cloning, Molecular; D003176:Complement C3 / Q000037:antagonists & inhibitors; D003169:Complement Inactivator Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006224:Cricetinae; D019288:Herpesvirus 8, Human / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008223:Lymphoma / Q000821:virology; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D018958:CD55 Antigens; D003176:Complement C3; D003169:Complement Inactivator Proteins; D014764:Viral Proteins