Tax deregulation of NF-kappaB2 p100 processing involves both beta-TrCP-dependent and -independent mechanisms.
Processing of the nf-kappab2 gene product p100 to generate p52 is a tightly regulated event, consistent with the fact that the processing product, p52, is hardly detected in most cell types, including T cells, although the precursor p100 is expressed abundantly in these cells. However, in T cells transformed by the human T-cell leukemia virus type I (HTLV-I), p100 processing is very active, resulting in high level expression of p52. Because overproduction of p52 is associated with lymphoid hyperplasia and transformation, deregulation of p100 processing may be part of the oncogenic mechanism of HTLV-I. We demonstrated previously that HTLV-I Tax oncoprotein is a potent inducer of p100 processing through specific targeting of IKKalpha via IKKgamma to p100 to trigger p100 phosphorylation and ubiquitination. In this study, we further show that Tax-mediated recruitment of IKKalpha to p100 requires serines 866 and 870 of p100, shown to be essential for inducible processing of p100. Upon interaction with p100, activated IKKalpha phosphorylates both N- and C-terminal serines of p100 (serines 99, 108, 115, 123 and 872), serving as a critical step in Tax-induced p100 processing. Using a genetic approach, we find that beta-transducin repeat-containing protein, a component of the SCF ubiquitin ligase complex, previously shown to be required for physiological p100 processing mediated by nuclear factor-kappaB-inducing kinase, is only partially involved in Tax-induced processing of p100. These results indicate that both beta-transducin repeat-containing protein-dependent and -independent mechanisms contribute to Tax-deregulated p100 processing, further suggesting the involvement of different mechanisms in cellular and viral pathways of p100 processing.
Qu
Zhaoxia
Z
Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Qing
Guoliang
G
Rabson
Arnold
A
Xiao
Gutian
G
D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D016356:Gene Products, tax / Q000378:metabolism*; D020868:Gene Silencing; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
D016356:Gene Products, tax; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D034741:RNA, Small Interfering; D025801:Ubiquitin; D012694:Serine; D044763:Ubiquitin-Conjugating Enzymes; D044843:SKP Cullin F-Box Protein Ligases; D005982:Glutathione Transferase