Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mimics Epstein-Barr virus EBNA1 immune evasion through central repeat domain effects on protein processing.
Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8 [HHV8]) and Epstein-Barr virus (EBV/HHV4) are distantly related gammaherpesviruses causing tumors in humans. KSHV latency-associated nuclear antigen 1 (LANA1) is functionally similar to the EBV nuclear antigen-1 (EBNA1) protein expressed during viral latency, although they have no amino acid similarities. EBNA1 escapes cytotoxic lymphocyte (CTL) antigen processing by inhibiting its own proteosomal degradation and retarding its own synthesis to reduce defective ribosomal product processing. We show here that the LANA1 QED-rich central repeat (CR) region, particularly the CR2CR3 subdomain, also retards LANA1 synthesis and markedly enhances LANA1 stability in vitro and in vivo. LANA1 isoforms have half-lives greater than 24 h, and fusion of the LANA1 CR2CR3 domain to a destabilized heterologous protein markedly decreases protein turnover. Unlike EBNA1, the LANA1 CR2CR3 subdomain retards translation regardless of whether it is fused to the 5' or 3' end of a heterologous gene construct. Manipulation of sequence order, orientation, and composition of the CR2 and CR3 subdomains suggests that specific peptide sequences rather than RNA structures are responsible for synthesis retardation. Although mechanistic differences exist between LANA1 and EBNA1, the primary structures of both proteins have evolved to minimize provoking CTL immune responses. Simple strategies to eliminate these viral inhibitory regions may markedly improve vaccine effectiveness by maximizing CTL responses.
Kwun
Hyun Jin
HJ
Molecular Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
da Silva
Suzane Ramos
SR
Shah
Ishita M
IM
Blake
Neil
N
Moore
Patrick S
PS
Chang
Yuan
Y
D000956:Antigens, Viral / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D000956:Antigens, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C109540:latency-associated nuclear antigen; D046988:Proteasome Endopeptidase Complex; C417029:EBV-encoded nuclear antigen 1