NRP/Optineurin Cooperates with TAX1BP1 to Potentiate the Activation of NF-κB by Human T-Lymphotropic Virus Type 1 Tax Protein

PLoS Pathogens

Frédégonde About¹  Sébastien A. Chevalier²  Renaud Mahieux³  Pierre-Olivier Vidalain³  David Flynn⁴  Alain Israël⁴  Josina Filipe⁵  Chloé Journo⁶  John N. Brady⁶  Frédéric Tangy⁶  Robert Weil⁷  Philippe V. Afonso⁷ 

[1] Ecole Normale Supérieure, Lyon, France;IFR 128 BioSciences Lyon-Gerland, Lyon, France;Laboratoire de Génomique Virale et Vaccination, Institut Pasteur, Paris, France;Laboratory of Cellular Oncology, NIH/NCI, Bethesda, Maryland, United States of America;Oncogenèse Rétrovirale, INSERM U758, Lyon, France;Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, CNRS URA 3015, Institut Pasteur, Paris, France;Unité de Signalisation Moléculaire et Activation Cellulaire, CNRS URA 2582, Institut Pasteur, Paris, France

关键词: Transcription factors;    Ubiquitination;    293T cells;    Small interfering RNAs;    Immunoprecipitation;    Golgi apparatus;    HeLa cells;    Two-hybrid screening;   

DOI  :  10.1371/journal.ppat.1000521

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Nuclear factor (NF)-κB is a major survival pathway engaged by the Human T-Lymphotropic Virus type 1 (HTLV-1) Tax protein. Tax1 activation of NF-κB occurs predominantly in the cytoplasm, where Tax1 binds NF-κB Essential Modulator (NEMO/IKKγ) and triggers the activation of IκB kinases. Several independent studies have shown that Tax1-mediated NF-κB 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-κB 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-κB 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-κB activation.

【 授权许可】

CC BY