HTLV-1 Tax protein recruitment into IKKε and TBK1 kinase complexes enhances IFN-I expression

Abstract

The Tax protein expressed by human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in the deregulation of cellular pathways involved in the immune response, inflammation, cell survival, and cancer. Many of these effects derive from Tax multiple interactions with host factors, including the subunits of the IKK-complex that are required for NF-κB activation. IKKɛ and TBK1 are two IKK-related kinases that allow the phosphorylation of interferon regulatory factors that trigger IFN type I gene expression. We observed that IKKɛ and TBK1 recruit Tax into cellular immunocomplexes. We also found that TRAF3, which regulates cell receptor signaling effectors, forms complexes with Tax. Transactivation analyses revealed that expression of Tax, in presence of IKKɛ and TBK1, enhances IFN-β promoter activity, whereas the activation of NF-κB promoter is not modified. We propose that Tax may be recruited into the TBK1/IKKɛ complexes as a scaffolding-adaptor protein that enhances IFN-I gene expression.

Suppression of Type I Interferon Production by Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax through Inhibition of IRF3 Phosphorylation

“…Our work directly contradicts two previous reports that claimed the activation of TBK1, IRF3, and IFN production by Tax (36,37). Our findings that IFN-␤ induction was compromised in HTLV-1-infected cells did not support the claim for activation of IFN induction.…”

“…Our findings that IFN-␤ induction was compromised in HTLV-1-infected cells did not support the claim for activation of IFN induction. Although the interaction of Tax with TBK1 was shown in our work and another recent study (37), the functional consequence reported in these two studies was completely opposite. Our finding on Tax inhibition of TBK1 activity was supported by a cluster of evidence obtained from different cells and using different experimental approaches.…”

“…In addition, Tax is known to interact with RIG-I, MDA5, TRIF, and RIP1, leading to the inhibition of IRF7 (35). Whereas these findings support the notion that Tax perturbs IFN production and signaling, both TBK1 and IRF3 have also been shown to be activated by Tax, leading to constitutive activation of IFN production (36,37). Thus, further investigations are required to clarify whether HTLV-1 and Tax might induce or suppress type I IFN production.…”

Identification of TBK1 and IKKε, the non-canonical IκB kinases, as crucial pro-survival factors in HTLV-1-transformed T lymphocytes

“…A recent report shows that Tax interacts with TBK1/IKKε in transfected HEK293 cells (20). Consistent with this finding, we found that Tax was co-precipitated with IKKε (Fig.…”

NF-κB and MicroRNA Deregulation Mediated by HTLV-1 Tax and HBZ

“…In line with their high functional domain homology, Tax-1 and Tax-2 show interesting similarities in their ability to form complexes with cytoplasmic factors. We demonstrated that both Tax-1 and Tax-2 form complexes with NF-κB pathway components NEMO and p65/RelA, the scaffold protein TAB2, and IKKε and TBK1, two IKK-related kinases that participate in both the NF-κB pathway and signaling pathways mediated by interferon regulatory factors (IRF) [103,104]. We propose that Tax-1 and Tax-2 may be recruited into the TBK1/IKK complexes as scaffolding-adaptor proteins and thereby enhance expression of IFN-inducible genes [104].…”