Volume 8 Supplement 1

15th International Conference on Human Retroviruses: HTLV and Related Viruses

Open Access

NF-κB hyper-activation by HTLV-1 Tax induces cellular senescence, but can be alleviated by the viral anti-sense protein HBZ

  • Huijun Zhi1,
  • Liangpeng Yang1,
  • Yu-Liang Kuo1,
  • Yik-Khuan Ho1,
  • Hsiu-Ming Shih2 and
  • Chou-Zen Giam1Email author
Retrovirology20118(Suppl 1):A200

https://doi.org/10.1186/1742-4690-8-S1-A200

Published: 6 June 2011

Activation of I-κB kinases (IKKs) and NF-κB by the human T lymphotrpic virus type 1

(HTLV-1) trans-activator/oncoprotein, Tax, is thought to promote cell proliferation and transformation. Paradoxically, expression of Tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors, p21CIP1/WAF1 and p27KIP1, which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21CIP1/WAF1-/p27KIP1-mediated senescence constitutes a checkpoint against IKK/NF-κB hyper-activation. Senescence induction by Tax is attenuated by mutations in Tax that reduce IKK/NF-κB activation and prevented by blocking NF-κB using a degradation-resistant mutant of I-κBα despite constitutive IKK activation. Small hairpin RNA-mediated knockdown indicates that RelA induces this senescence program by acting upstream of the anaphase promoting complex and RelB to stabilize p27KIP1 protein and p21CIP1/WAF1 mRNA respectively. Finally, we show that downregulation of NF-κB by the HTLV-1 anti-sense protein, HBZ, delay or prevent the onset of Tax-induced senescence. We propose that the balance between Tax and HBZ expression determines the outcome of HTLV-1 infection. Robust HTLV-1 replication and elevated Tax expression drive IKK/NF-κB hyperactivation and trigger senescence. HBZ, however, modulates Tax-mediated viral replication and NF-κB activation, thus allowing HTLV-1-infected cells to proliferate, persist, and evolve. Finally, inactivation of the senescence checkpoint can facilitate persistent NF-κB activation and leukemogenesis.

Authors’ Affiliations

(1)
Department of Microbiology and Immunology Uniformed Services, University of the Health Sciences
(2)
Institute of Biomedical Sciences, Academia Sinica

Copyright

© Zhi et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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