Inactivation of IkappaBbeta by the tax protein of human T-cell leukemia virus type 1: a potential mechanism for constitutive induction of NF-kappaB.
In resting T lymphocytes, the transcription factor NF-kappaB is sequestered in the cytoplasm via interactions with members of the I kappa B family of inhibitors, including IkappaBalpha and IkappaBbeta. During normal T-cell activation, IkappaBalpha is rapidly phosphorylated, ubiquitinated, and degraded by the 26S proteasome, thus permitting the release of functional NF-kappaB. In contrast to its transient pattern of nuclear induction during an immune response, NF-kappaB is constitutively activated in cells expressing the Tax transforming protein of human T-cell leukemia virus type I (HTLV-1). Recent studies indicate that HTLV-1 Tax targets IkappaBalpha to the ubiquitin-proteasome pathway. However, it remains unclear how this viral protein induces a persistent rather than transient NF-kappaB response. In this report, we provide evidence that in addition to acting on IkappaBalpha, Tax stimulates the turnover Of IkappaBbeta via a related targeting mechanism. Like IkappaBalpha, Tax-mediated breakdown of IkappaBbeta in transfected T lymphocytes is blocked either by cell-permeable proteasome inhibitors or by mutation Of IkappaBbeta at two serine residues present within its N-terminal region. Despite the dual specificity of HTLV-1 Tax for IkappaBalpha and IkappaBbeta at the protein level, Tax selectively stimulates NF-kappaB-directed transcription of the IkappaBalpha gene. Consequently, IkappaBbeta protein expression is chronically downregulated in HTLV-1-infected T lymphocytes. These findings with IkappaBbeta provide a potential mechanism for the constitutive activation of NF-kappaB in Tax-expressing cells.
McKinsey
T A
TA
Howard Hughes Medical Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Brockman
J A
JA
Scherer
D C
DC
Al-Murrani
S W
SW
Green
P L
PL
Ballard
D W
DW
D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015696:Gene Products, tat / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D007700:Kinetics; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012694:Serine; D013601:T-Lymphocytes / Q000378:metabolism; D014162:Transfection
D017931:DNA Primers; D004268:DNA-Binding Proteins; D015696:Gene Products, tat; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D011994:Recombinant Proteins; D012694:Serine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex