The Tax oncoprotein of human T cell leukemia virus type 1 constitutively activates transcription factor NF-B by a mechanism involving Tax-induced phosphorylation of IB␣, a labile cytoplasmic inhibitor of NF-B. To trigger this signaling cascade, Tax associates stably with and persistently activates a cellular IB kinase (IKK) containing both catalytic (IKK␣ and IKK␤) and noncatalytic (IKK␥) subunits. We now demonstrate that IKK␥ enables Tax to dock with the IKK␤ catalytic subunit, resulting in chronic IB kinase activation. Mutations in either IKK␥ or Tax that prevent formation of these higher order Tax⅐IKK complexes also interfere with the ability of Tax to induce IKK␤ catalytic function in vivo. Deletion mapping studies indicate that amino acids 1-100 of IKK␥ are required for this Tax targeting function. Together, these findings identify IKK␥ as an adaptor protein that directs the stable formation of pathologic Tax⅐IKK complexes in virally infected T cells.During an adaptive immune response, antigen-stimulated CD4 ϩ T lymphocytes become committed to an activation program that triggers a transient phase of clonal expansion (1). In contrast, infection with human T cell leukemia virus type 1 (HTLV-1) 1 can lead to the loss of cell cycle control and development of an aggressive malignancy called adult T cell leukemia (2). The Tax oncoprotein encoded by HTLV-1 stimulates the constitutive nuclear expression of transcription factor NF-B, which regulates antigen-directed T cell proliferation (3, 4).Studies with Tax-transgenic mice suggest that this viral/host interaction is required to maintain the transformed phenotype of HTLV-1-infected cells (5).In quiescent T cells, the activity of NF-B is controlled from the cytoplasmic compartment by virtue of its signal-dependent interaction with inhibitors, including IB␣ (6). Recent studies have identified two cytokine-inducible IB kinases (IKKs), termed IKK␣ and IKK␤, that target IB␣ for degradation via phosphorylation at Ser-32 and Ser-36 (7). These two kinases form heterodimers and function as catalytic subunits within a 700 -900-kDa multicomponent complex (8). Whereas IKK␣ and IKK␤ are activated transiently in cells treated with the cytokine tumor necrosis factor-␣ (TNF) (8 -10), Tax induces their constitutive expression in HTLV-1-infected T cells (11,12). We have recently found that Tax-induced activation of both IKK and NF-B requires the formation of Tax⅐IKK complexes (12). However, the precise mechanism of Tax action on IKKs remains unclear.Here we provide several lines of experimental evidence indicating that Tax-directed IKK activation is mediated by IKK␥ (also called NEMO, IKKAP1, or FIP-3), a recently identified subunit of TNF-responsive IKKs whose precise signaling function is unknown (13-16). First, interference with IKK␥ expression in T cell transfectants inhibits Tax-mediated activation of NF-B. Second, IKK␥ and Tax interact stably in the context of a high molecular mass IB kinase derived from HTLV-1-infected T cells. Third, overexpression of IKK␥ in vivo is suffic...

The human endogenous retrovirus K (HERV-K) family of endogenous retroviruses consists of Ϸ50 proviral copies per haploid human genome. Herein, the HERV-Ks are shown to encode a sequence-specific nuclear RNA export factor, termed K-Rev, that is functionally analogous to the HIV-1 Rev protein. Like HIV-1 Rev, K-Rev binds to both the Crm1 nuclear export factor and to a cis-acting viral RNA target to activate nuclear export of unspliced RNAs. Surprisingly, this HERV-K RNA sequence, which is encoded within the HERV-K long terminal repeat, is also recognized by HIV-1 Rev. These data provide surprising evidence for an evolutionary link between HIV-1 and a group of endogenous retroviruses that first entered the human genome Ϸ30 million years ago. During the retroviral replication cycle, the initial genome length viral transcript must be expressed in both fully spliced and incompletely spliced forms. However, cells have developed mechanisms to prevent the nuclear export of RNAs that retain splice sites, i.e., pre-mRNAs, via the endogenous mRNA export pathway. Retroviruses have therefore evolved in ways that enable them to target their incompletely spliced transcripts to alternative nuclear export pathways (reviewed in refs. 1 and 2). Thus, HIV-1 encodes a protein termed Rev that recruits a cellular nuclear export factor, termed Crm1, to the Rev response element (RRE), a structured RNA target sequence encoded within the viral genome (3-6). Nuclear export of incompletely spliced viral RNAs requires the recruitment of multiple Rev and Crm1 molecules to the RRE and depends on the GTP-bound form of the cellular Ran protein, which mediates the Rev-Crm1 interaction (4, 6). Although most other complex retroviruses also encode Rev-like proteins, simple retroviruses lack a Rev equivalent and instead rely on the direct recruitment of a host nuclear RNA export factor to a cis-acting RNA target termed a constitutive transport element (CTE; ref. 7). In the case of the Mason-Pfizer monkey virus (MPMV) CTE, this factor has been identified as the host protein Tap (8, 9). Importantly, CTE͞Tap-mediated nuclear RNA export is independent of Crm1 function (9-11).Endogenous retroviruses are encoded within the genomes of all higher eukaryotes and arose from the infection of germ cells by exogenous retroviruses (12, 13). These infections generally occurred in the distant past and most endogenous retroviruses have suffered inactivating mutations or deletions over time. The human endogenous retrovirus K (HERV-K) family is represented in the human genome by Ϸ50 more-or-less full-length proviruses and over 1,000 solitary long terminal repeats (LTRs) (12). The HERV-Ks first entered the primate genome shortly after the split of new world and old world monkeys (i.e., Ն30 million years ago) with some evolutionarily more recent HERV-K insertions postdating the human͞chimpanzee division (i.e., Ϸ5 million years ago; ref. 14). The HERV-Ks have no known close exogenous relative, although they do show some homology to mouse mammary tumor virus and to the rece...

Nuclear mRNA export mediated by the human protein TAP requires a carboxy-terminal domain that directly interacts with components of the nuclear pore complex. Here we demonstrate that NXF3, a human RNA binding protein related to TAP, lacks this domain yet retains the ability to export tethered RNA transcripts and to shuttle between the nucleus and the cytoplasm. NXF3 contains a novel Crm1-dependent nuclear export signal that compensates in cis for the loss of the nuclear pore targeting domain. NXF3-dependent RNA export is therefore blocked by Crm1-specific inhibitors that do not affect TAP function. Thus, while the related TAP and NXF3 proteins are both capable of mediating nuclear RNA export, they do so via unrelated export pathways.