The nuclear factor-κB (NF-κB) family of transcription factors plays a central part in the host response to infection by microbial pathogens, by orchestrating the innate and acquired host immune responses. The NF-κB proteins are activated by diverse signalling pathways that originate from many different cellular receptors and sensors. Many successful pathogens have acquired sophisticated mechanisms to regulate the NF-κB signalling pathways by deploying subversive proteins or hijacking the host signalling molecules. Here, we describe the mechanisms by which viruses and bacteria micromanage the host NF-κB signalling circuitry to favour the continued survival of the pathogen.

Modulation of NF-κB signalling by microbial pathogens

Human T cell lymphotropic virus type 1 (HTLV-1) has been identified as the causative agent of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus infects between 15 and 20 million people worldwide of which approximately 2 to 5% develop ATL. The past 35 years of research have yielded significant insight into the pathogenesis of HTLV-1, including the molecular characterization of Tax, the viral transactivator and oncoprotein. In spite of these efforts, the mechanisms of oncogenesis of this pleiotropic protein remain to be fully elucidated. In this review, we illustrate the multiple oncogenic roles of Tax by summarizing a recent body of literature that refines our understanding of cellular transformation. A focused range of topics are discussed in this review including Tax-mediated regulation of the viral promoter and other cellular pathways, particularly the connection of the NF-κB pathway to both post-translational modifications of Tax and sub-cellular localization. Specifically, recent research on polyubiquitination of Tax as it relates to the activation of the IkappaB kinase (IKK) complex is highlighted. Regulation of the cell cycle and DNA damage responses due to Tax are also discussed, including Tax interaction with minichromosome maintenance proteins and the role of Tax in chromatin remodeling. The recent identification of HTLV-3 has amplified the importance of the characterization of emerging viral pathogens. The challenge of the molecular determination of pathogenicity and malignant disease of this virus lies in the comparison of the viral transactivators of HTLV-1, -2, and -3 in terms of transformation and immortalization. Consequently, differences between the three proteins are currently being studied to determine what factors are required for the differences in tumorogenesis.

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HTLV Tax: A Fascinating Multifunctional Co-Regulator of Viral and Cellular Pathways

Lipids in host-pathogen interactions: pathogens exploit the complexity of the host cell lipidome.

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

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NRP/Optineurin Cooperates with TAX1BP1 to potentiate the activation of NF-kappaB by human T-lymphotropic virus type 1 tax protein.

Summary: Viruses and hosts are involved in a continuing ‘arms race’. The body deploys multiple defenses; however, viruses utilize generally superior and more rapidly evolving tactics for negating host immune surveillance and viral clearance. In the case of the two major pathogenic human retroviruses, human immunodeficiency virus-1 (HIV-1) and human T-lymphotrophic virus-I (HTLV-I), the nuclear factor-κB (NF-κB) transcription factor plays a key role in the host’s anti-viral responses involving both the innate and adaptive arms of the immune response. Similarly, these retroviruses capably exploit NF-κB for their replication, spread, and pathogenic functions. In this review, we discuss the dynamic and intimate interplay that occurs between NF-κB and the HTLV-I and HIV-1 retroviral pathogens.

Jiannan Huang

Papers

HTLV-1 Tax Is a Critical Lipid Raft Modulator That Hijacks IκB Kinases to the Microdomains for Persistent Activation of NF-κB