Human T Cell Lymphotropic Virus 1 Manipulates Interferon Regulatory Signals by Controlling the TAK1-IRF3 and IRF4 Pathways

Abstract

We previously reported that human T cell lymphotropic virus 1 (HTLV-1) Tax oncoprotein constitutively activates transforming growth factor-␤-activated kinase 1 (TAK1). Here, we established Tax (5) and cytosolic viral RNA sensors, such as RIG-I (6) and MDA5 (7). In contrast, IRF4, another member of the IRF family that is preferentially expressed in lymphoid cells, was first identified as a transcription factor that negatively regulates the activity of IFN-regulated genes (8) and TLR signaling (9). Human T cell lymphotropic virus type 1 (HTLV-1) is known as the cause of adult T cell leukemia/lymphoma (ATLL). HTLV-1-derived oncoprotein Tax is thought to be a key molecule of ATLL onset and has many pathological functions such as virus replication, immortalization of host cells, and activation of several transcriptional factors and signal transduction molecules, including NF-B, cAMP-response element-binding protein, and phosphoinositide 3-kinase-Akt in host CD4 ϩ T cells (10 -12). We have recently found Tax-dependent constitutive activation of the TAK1-MAPK pathway (13). TAK1 is known as a key kinase leading to NF-B in tumor necrosis factor-␣ and interleukin-1 signaling pathways (14, 15); however, it is dispensable in Tax-dependent constitutive NF-B activation (13). TAK1 has been demonstrated to participate in TLR-mediated activation of NF-B (16) but not the TBK1-IRF3/7 pathway (17, 18); however, the role of constitutive TAK1 activation in IFN-regulatory signals triggered by HTLV-1 is still largely unknown.In the present study, we demonstrated that Tax-dependent TAK1 activation induces TBK1-IRF3 activation and the expression of several IFN-inducible genes, including CXCL10 and CCL5. Moreover, IRF4, overexpressed in HTLV-1-infected cells in a Tax-independent manner, negatively controls the transcriptional regulation of these genes.

Oncogenic IRFs Provide a Survival Advantage for Epstein-Barr Virus- or Human T-Cell Leukemia Virus Type 1-Transformed Cells through Induction of BIC Expression

“…Other IRFs that are important players in the production of type I IFNs, including at least IRF1, -3, and -7, IRF7, -4, and -2, three IRFs with oncogenic properties, are associated with EBV latency and may contribute to EBV oncogenesis. Overwhelming evidence also shows that IRF4 is overexpressed in HTLV1-infected cells and associated tumors (51,58,61,74), suggesting that IRF4 may play a key role in HTLV1 tumorigenesis. Regulation of IRF4 expression in the context of HTLV1 infection is complicated.…”

“…Among IRFs, IRF2, -4, and -7 have oncogenic potentials (41). IRF4 is overexpressed in EBVtransformed cells (73) and in multiple myeloma (24,57), as well as in human T-cell leukemia virus type 1 (HTLV1)-infected cell lines and associated adult T-cell lymphoma/leukemia (ATLL) (51,58,61,74). IRF7 has been shown to be associated with EBV latency and is overexpressed in a subset of EBV-positive and -negative lymphomas/leukemias (41).…”

Polymorphic Nature of Human T-Cell Leukemia Virus Type 1 Particle Cores as Revealed through Characterization of a Chronically Infected Cell Line

“…Likewise, IRF4 was found to be constitutively expressed in ATL as opposed to nonlymphocytic HTLV-1 infection (48). A number of studies have linked activating mutations and high levels of expression of IRF4 with HTLV-1 infection, with IRF4 expression resulting in reduced expression levels of genes previously shown to be dysregulated in ATL cases (48)(49)(50)(51)(52)(53). As proviral integration was found in the 5= ends of both of these genes, it is possible that integration may alter gene expression and thus may have contributed to transformation or ATL.…”

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…232 Both phenylephrine-or endothelin-1-stimulated cardiomyocyte enlargement in vitro and AB-induced cardiac hypertrophy in vivo have identified the bona fide suppressive function of A20 on hypertrophic responses based on its negative regulation of NF-κB and the transforming growth factor-beta (TGF-β)-activated kinase 1 (TAK1)-dependent JNK/p38 signaling cascade. [233][234][235] Suzuki et al 236 reported that A20 overexpression markedly induced the activation of IRF3 in a TAK1-dependent manner that was negatively regulated by IRF4 in response to stimulation with human T-cell lymphotropic virus. These studies suggested that A20/TAK1/IRFs might form a crucial signaling cascade to regulate cardiac remodeling; however, this hypothesis must be further confirmed.…”