title: Complex alternative cytoplasmic protein isoforms of the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 generated through noncanonical translation initiation.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) latency associated-nuclear antigen 1 (LANA1) protein is constitutively expressed in all KSHV-infected cells, as well as in all forms of KSHV-associated malignancies. LANA1 is a multifunctional KSHV oncoprotein containing multiple repeat sequences that is important for viral episome maintenance and the regulation of cellular and viral gene expression. We characterize here multiple LANA1 isoforms and show that ∼50% of LANA1 is naturally generated as N-terminally truncated shoulder proteins that are detected on SDS-PAGE as faster-migrating shoulder bands designated LANA1(S). Higher-molecular-weight LANA1(S) isoforms initiate downstream at noncanonical sites within the N-terminal region, whereas lower-molecular-weight LANA1(S) isoforms initiate downstream within the central repeat 1 domain. LANA1(S) proteins lack an N-terminal nuclear localization signal motif, and some isoforms differ from full-length, canonical LANA1 by localizing to perinuclear and cytoplasmic sites. Although LANA1 has until now been assumed to be solely active in the nucleus, this finding indicates that this major KSHV oncoprotein may have cytoplasmic activities as well. KSHV overcomes its limited genetic coding capacity by generating alternatively initiated protein isoforms that may have distinct biological functions.
authors.affiliation: Cancer Virology Program, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Tuna
authors.initials: T
authors.lastname: Toptan
authors.forename: Lidia
authors.initials: L
authors.lastname: Fonseca
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kwun
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chang
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Moore
mesh_terms: D000956:Antigens, Viral / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D000956:Antigens, Viral; D004279:DNA, Viral; D009687:Nuclear Proteins; D020033:Protein Isoforms; C109540:latency-associated nuclear antigen