Cellular and viral protein interactions regulating I kappa B alpha activity during human retrovirus infection

NF‐κB/Rel transcription factors participate in the activation of numerous genes involved in immune regulation/inflammation including cytokines, cell surface receptors, adhesion molecules, and acute phase proteins. NF‐κB activity is controlled by inhibitory proteins, IκBs, that maintain the DNA‐binding forms of NF‐κB in an inactive state in the cytoplasm. Many viruses, including the human retroviruses HIV‐1 and HTLV‐1, also utilize the NF‐κB/IκB pathway to their transcriptional advantage during viral infection. Our recent studies have focused on the IκBα inhibitor and have characterized several protein interactions that modulate the functional activity of IκBα during human retrovirus infection. In this article, we summarize recent studies demonstrating that (1) chronic HIV‐1 infection of human myelomonoblastic PLB‐985 cells leads to constitutive NF‐κB activity, activated in part due to enhanced IκBα turnover and increased NF‐κB/Rel production; (2) HTLV‐1 Tax protein physically associates with the IκBα protein in vivo and in vitro and also mediates a 20‐ to 40‐fold stimulation of NF‐κB DNA binding activity mediated via an enhancement of NF‐κB dimer formation; (3) casein kinase II phosphorylates IκBα at multiple sites in the C‐terminal PEST domain and regulates IκBα function; (4) transdominant forms of IκBα, mutated in critical Ser or Thr residues required for inducer‐mediated (S32A,S36A) and/or constitutive phosphorylation block HIV LTR trans‐activation and also effectively inhibit HIV‐1 multiplication in a single cycle infection model; and (5) the amino‐terminal 55aa of IκBα (NIK) interacts with the human homologue of dynein light chain 1, a small 9‐kDa human homologue of the dynein light chain protein involved in microtubule and cytoskeletal dynamics. Together, our results highlight a number of intriguing molecular interactions between IκBα and cellular or viral proteins that modulate transcription factor activity and nuclear‐cytoplasmic flow of host proteins. J. Leukoc. Biol. 62: 82–92; 1997.