Two carboxyl-terminal activation regions of Epstein-Barr virus latent membrane protein 1 activate NF-kappaB through distinct signaling pathways in fibroblast cell lines.
Latent membrane protein 1 (LMP1), an Epstein-Barr virus transforming protein, is able to activate NF-kappaB through its carboxyl-terminal activation region 1 (CTAR1) and 2 (CTAR2), but the exact role of each domain is not fully understood. Here we show that LMP1 activates NF-kappaB in different NF-kappaB essential modulator (NEMO)-defective cell lines, but not in cells lacking both IkappaB kinase 1 (IKK1) and 2 (IKK2). Mutational studies reveal that CTAR1, but not CTAR2, mediates NEMO-independent NF-kappaB activation and that this process largely depends on IKK1. Retroviral expression of LMP1 mutants in cells lacking either functional NF-kappaB inducing kinase (NIK), NEMO, IKK1, or IKK2 further illustrates distinct signals from the two activation regions of LMP1 for persistent NF-kappaB activation. One originates in CTAR2, operates through the canonical NEMO-dependent pathway, and induces NFKB2 p100 production; the second signal originates in CTAR1, utilizes NIK and IKK1, and induces the processing of p100. Our results thus help clarify how two functional domains of LMP1 persistently activate NF-kappaB through distinct signaling pathways.
Saito
Naohito
N
Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan.
Courtois
Gilles
G
Chiba
Ayako
A
Yamamoto
Norio
N
Nitta
Takeshi
T
Hironaka
Noriko
N
Rowe
Martin
M
Yamamoto
Naoki
N
Yamaoka
Shoji
S
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000737:chemistry; D051550:I-kappa B Kinase; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000502:physiology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D014763:Viral Matrix Proteins; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase