NRP/Optineurin Cooperates with TAX1BP1 to potentiate the activation of NF-kappaB by human T-lymphotropic virus type 1 tax protein.
Nuclear factor (NF)-kappaB is a major survival pathway engaged by the Human T-Lymphotropic Virus type 1 (HTLV-1) Tax protein. Tax1 activation of NF-kappaB occurs predominantly in the cytoplasm, where Tax1 binds NF-kappaB Essential Modulator (NEMO/IKKgamma) and triggers the activation of IkappaB kinases. Several independent studies have shown that Tax1-mediated NF-kappaB 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-kappaB 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-kappaB 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-kappaB activation.
Journo
Chloé
C
Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, CNRS URA 3015, Institut Pasteur, Paris, France.
Filipe
Josina
J
About
Frédégonde
F
Chevalier
Sébastien A
SA
Afonso
Philippe V
PV
Brady
John N
JN
Flynn
David
D
Tangy
Frédéric
F
Israël
Alain
A
Vidalain
Pierre-Olivier
PO
Mahieux
Renaud
R
Weil
Robert
R
D001665:Binding Sites; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D026901:Membrane Transport Proteins; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D035582:Transcription Factor TFIIIA / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination
D018797:Cell Cycle Proteins; D016356:Gene Products, tax; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; C409460:OPTN protein, human; C120635:TAX1BP1 protein, human; D035582:Transcription Factor TFIIIA; C514970:tax protein, Human T-lymphotrophic virus 1