HnRNPA1 and HuR , but not PTB , modulate cap‐independent translation initiation from sense and antisense human T‐cell lymphotropic virus type 1 mRNA s

The human T‐cell lymphotropic virus type 1 (HTLV‐1) causes adult T‐cell leukemia and HTLV‐associated myelopathy/tropical spastic paraparesis. HTLV‐1 transcribes sense and two antisense messenger RNAs (mRNAs). The spliced and unspliced antisense mRNA encode the HTLV‐1 basic zipper factor (HBZ). The sense mRNA can initiate translation using a cap‐ or internal ribosomal entry site (IRES)‐mediated mechanism (HTLV‐1 IRES). The spliced antisense mRNA initiates translation via the sHBZ IRES. Using bicistronic vectors harboring the 5′‐untranslated region of the HTLV‐1 sense or spliced antisense mRNAs in their intercistronic space, we evaluated the role of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), ELAV‐like protein 1 (ELAVL1; also known as HuR), and polypyrimidine tract‐binding protein 1 (PTB) as regulators of the HTLV‐1 IRES and sHBZ IRES function. Results show that PTB is not an IRES‐transacting factor (ITAF) for either IRES, whereas hnRNPA1 promotes both. However, protein arginine N‐methyltransferase 5 (PRMT5)‐induced symmetrical dimethylation of arginine residues in hnRNPA1, required to stimulate the HTLV‐1 IRES, plays no role in sHBZ IRES activity. HuR overexpression reduces both HTLV‐1 IRES and sHBZ IRES activity. The effect of hnRNPA1 and HuR over the IRESs is lost when both proteins are overexpressed together. When heterogeneous nuclear ribonucleoprotein K (hnRNPK), an ITAF for the HTLV‐1 IRES but not for the sHBZ IRES, is overexpressed with HuR, HTLV‐1 IRES is stimulated, whereas sHBZ IRES activity is reduced. Consequently, ITAFs or combinations of ITAFs differentially modulated the HTLV‐1 IRES and sHBZ IRES activity, indicating that these IRESs are under translational control mediated by different subsets of ITAFs.