TRAF activation of C/EBPbeta (NF-IL6) via p38 MAPK induces HIV-1 gene expression in monocytes/macrophages.
C/EBPbeta plays a pivotal role in activation of human immunodeficiency virus type 1 (HIV-1) in monocytes/macrophages. However, mechanisms for functional regulation of C/EBPbeta remain uncharacterized. Previous studies indicated that NF-kappaB activation by tumor necrosis factor (TNF) receptor family, which activates TNF receptor associated factor (TRAF), induces HIV-1 expression. We found that TRAF signals activate HIV-1 LTR with mutations of NF-kappaB sites in promonocytic cell line U937, suggesting existence of an alternative HIV-1 activating pathway. In this study, we have characterized the signal transduction pathway of TRAF other than that leading to NF-kappaB, using U937 cell line, and its subline, U1, which is chronically infected by HIV-1. We show that signals downstream of TRAF2 and TRAF5 activate p38 MAPK, which directly phosphorylates C/EBPbeta, and that activation of p38 MAPK potently activates C/EBPbeta-mediated induction of HIV-1 gene expression. We also show TRAF2 and TRAF5 are expressed in monocytes/macrophages of spleen samples from HIV-1 infected patients. Identification of TRAF-p38 MAPK-CEBPbeta pathway provides a new target for controlling reactivation of latent HIV-1 in monocytes/macrophages.
Horie
Ryouichi
R
Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
Ishida
Takaomi
T
Maruyama-Nagai
Masae
M
Ito
Kinji
K
Watanabe
Mariko
M
Yoneyama
Akiko
A
Higashihara
Masaaki
M
Kimura
Satoshi
S
Watanabe
Toshiki
T
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000821:virology; D009000:Monocytes / Q000821:virology; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D013154:Spleen / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D048015:TNF Receptor-Associated Factor 5 / Q000378:metabolism*; D014775:Virus Activation; D017735:Virus Latency; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D022782:CCAAT-Enhancer-Binding Protein-beta; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D048051:p38 Mitogen-Activated Protein Kinases