Activation of CD21 and CD23 gene expression by Kaposi's sarcoma-associated herpesvirus RTA.
Epstein-Barr virus (EBV) EBNA2 and Kaposi's sarcoma-associated herpesvirus (KSHV) replication and transcription activator (RTA) are recruited to their responsive elements through interaction with a Notch-mediated transcription factor, RBP-Jkappa. In particular, RTA and EBNA2 interactions with RBP-Jkappa are essential for the lytic replication of KSHV and expression of B-cell activation markers CD21 and CD23a, respectively. Here, we demonstrate that like EBV EBNA2, KSHV RTA strongly induces CD21 and CD23a expression through RBP-Jkappa binding sites in the first intron of CD21 and in the CD23a core promoter, respectively. However, unlike EBV EBNA2, which alters immunoglobulin mu (Igmu) and c-myc gene expression, RTA did not affect Igmu and c-myc expression, indicating that KSHV RTA targets the Notch signal transduction pathway in a manner similar to but distinct from that of EBV EBNA2. Furthermore, RTA-induced expression of CD21 glycoprotein, which is an EBV receptor, efficiently facilitated EBV infection. In addition, RTA-induced CD23 glycoprotein underwent proteolysis and gave rise to soluble CD23 (sCD23) molecules in B lymphocytes and KSHV-infected primary effusion lymphocytes. sCD23 then stimulated primary human lymphocytes. These results demonstrate that cellular CD21 and CD23a are common targets for B lymphotropic gammaherpesviruses and that KSHV RTA regulates RBP-Jkappa-mediated cellular gene expression, which ultimately provides a favorable milieu for viral reproduction in the infected host.
Chang
Heesoon
H
Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Dr., Southborough, MA 01772, USA.
Gwack
Yousang
Y
Kingston
Dior
D
Souvlis
John
J
Liang
Xiaozhen
X
Means
Robert E
RE
Cesarman
Ethel
E
Hutt-Fletcher
Lindsey
L
Jung
Jae U
JU
D015703:Antigens, CD / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D017464:Receptors, Complement 3d / Q000235:genetics*; D017455:Receptors, IgE / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics*; D014779:Virus Replication
D015703:Antigens, CD; D017931:DNA Primers; D017874:Immediate-Early Proteins; D017464:Receptors, Complement 3d; D017455:Receptors, IgE; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014764:Viral Proteins