Journal
PLOS PATHOGENS
Volume 5, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1000521
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Funding
- Ecole Normale Superieure de Lyon
- CNRS
- Ministere de la Recherche
- Fundacao para a Ciencia e a Tecnologia PhD fellowship
- Fulbright Fellowship through the U. S. Department of State Bureau of Educational and Cultural Affairs
- Pasteur Institute [PTR214]
- Rubicon FP6 European Network of Excellence
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Nuclear factor (NF)-kappa B is a major survival pathway engaged by the Human T-Lymphotropic Virus type 1 (HTLV-1) Tax protein. Tax1 activation of NF-kappa B occurs predominantly in the cytoplasm, where Tax1 binds NF-kB Essential Modulator (NEMO/IKK gamma) and triggers the activation of I kappa B kinases. Several independent studies have shown that Tax1-mediated NF-kappa B activation is dependent on Tax1 ubiquitination. Here, we identify by co-immunoprecipitation assays NEMO-Related Protein (NRP/Optineurin) as a binding partner for Tax1 in HTLV-1 infected and Tax1/NRP co-expressing cells. Immunofluorescence studies reveal that Tax1, NRP and NEMO colocalize in Golgi-associated structures. The interaction between Tax1 and NRP requires the ubiquitin-binding activity of NRP and the ubiquitination sites of Tax1. In addition, we observe that NRP increases the ubiquitination of Tax1 along with Tax1-dependent NF-kappa B signaling. Surprisingly, we find that in addition to Tax1, NRP interacts cooperatively with the Tax1 binding protein TAX1BP1, and that NRP and TAX1BP1 cooperate to modulate Tax1 ubiquitination and NF-kappa B activation. Our data strongly suggest for the first time that NRP is a critical adaptor that regulates the assembly of TAX1BP1 and post-translationally modified forms of Tax1, leading to sustained NF-kappa B activation.
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