title: The Werner Protein Acts as a Coactivator of Nuclear Factor κB (NF-κB) on HIV-1 and Interleukin-8 (IL-8) Promoters.
abstract: The Werner syndrome helicase (WRN) plays a role in maintaining genomic stability. The lack of WRN results in Werner syndrome, a rare autosomal recessive genetic disorder, which causes premature aging accompanied by many complications such as rare forms of cancer and type 2 diabetes. However, the underlying mechanisms of these complications, arising due to the loss of WRN, are poorly understood. In this study, we demonstrated the function of WRN in transcriptional regulation of NF-κB targets. WRN physically interacts via its RecQ C-terminal (RQC) domain with the Rel homology domain of both the RelA (p65) and the p50 subunits of NF-κB. In the steady state, WRN is recruited to HIV-1 long terminal repeat (LTR), a typical NF-κB-responsive promoter, as well as the p50/p50 homodimer, in an NF-κB site-dependent manner. The amount of WRN on LTR increased along with the transactivating RelA/p50 heterodimer in response to TNF-α stimulation. Further, a knockdown of WRN reduced the transactivation of LTR in exogenous RelA/p50-introduced or TNF-α-stimulated cells. Additionally, knockdown of WRN reduced TNF-α stimulation-induced activation of the endogenous promoter of IL-8, an NF-κB-responsive gene, and WRN increased its association with the IL-8 promoter region together with RelA/p50 after TNF-α stimulation. In conjunction with studies that have shown NF-κB to be a key regulator of aging and inflammation, our results indicate a novel role of WRN in transcriptional regulation. Along with NF-κB, the loss of WRN is expected to result in incorrect regulation of downstream targets and leads to immune abnormalities and homeostatic disruption.
authors.affiliation: From the Laboratory of Virology, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 and mizutanit@bikaken.or.jp.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: From the Laboratory of Virology, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 and.
authors.forename: Aya
authors.initials: A
authors.lastname: Ishizaka
authors.affiliation: GeneCare Research Institute Co., Ltd., 19-2 Kajiwara, Kamakura, Kanagawa 247-0063, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Furuichi
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D052002:NF-kappa B p50 Subunit / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014898:Werner Syndrome / Q000235:genetics* / Q000473:pathology; D000071657:Werner Syndrome Helicase
chemical_list: D016209:Interleukin-8; D052002:NF-kappa B p50 Subunit; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase
keywords: IL-8; NF-kB transcription factor; WRN; Werner syndrome; aging; human immunodeficiency virus (HIV); retrovirus; viral transcription