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: Taketoshi Mizutani, Aya Ishizaka, Yasuhiro Furuichi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 30 Pg. 18391-9 (Jul 24 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26037922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Interleukin-8
• NF-kappa B p50 Subunit
• RELA protein, human
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• Exodeoxyribonucleases
• RecQ Helicases
• WRN protein, human
• Werner Syndrome Helicase

Topics

• Aging (genetics, pathology)
• Exodeoxyribonucleases (genetics, metabolism)
• HIV-1 (genetics)
• HeLa Cells
• Humans
• Interleukin-8 (biosynthesis, genetics)
• NF-kappa B p50 Subunit (biosynthesis, genetics)
• Promoter Regions, Genetic
• RecQ Helicases (genetics, metabolism)
• Transcription Factor RelA (biosynthesis, genetics)
• Transcription, Genetic
• Tumor Necrosis Factor-alpha (pharmacology)
• Werner Syndrome (genetics, pathology)
• Werner Syndrome Helicase