title: Cellular and viral protein interactions regulating I kappa B alpha activity during human retrovirus infection.
abstract: NF-kappa B/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-kappa B activity is controlled by inhibitory proteins, I kappa Bs, that maintain the DNA-binding forms of NF-kappa B in an inactive state in the cytoplasm. Many viruses, including the human retroviruses HIV-1 and HTLV-1, also utilize the NF-kappa B/I kappa B pathway to their transcriptional advantage during viral infection. Our recent studies have focused on the I kappa B alpha inhibitor and have characterized several protein interactions that modulate the functional activity of I kappa B alpha during human retrovirus infection. In this article, we summarise recent studies demonstrating that (1) chronic HIV-1 infection of human myelomonoblastic PLB-985 cells leads to constitutive NF-kappa B activity, activated in part due to enhanced I kappa B alpha turnover and increased NF-kappa B/Rel production; (2) HTLV-1 Tax protein physically associates with the I kappa B alpha protein in vivo and in vitro and also mediates a 20- to 40-fold stimulation of NF-kappa B DNA binding activity mediated via an enhancement of NF-kappa B dimer formation; (3) casein kinase II phosphorylates I kappa B alpha at multiple sites in the C-terminal PEST domains and regulates I kappa B alpha function; (4) transdominant forms of I kappa B alpha, 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 I kappa B alpha (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 I kappa B alpha and cellular or viral proteins that modulate transcription factor activity and nuclear-cytoplasmic flow of host proteins.
authors.affiliation: Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Hiscott
authors.forename: P
authors.initials: P
authors.lastname: Beauparlant
authors.forename: P
authors.initials: P
authors.lastname: Crepieux
authors.forename: C
authors.initials: C
authors.lastname: DeLuca
authors.forename: H
authors.initials: H
authors.lastname: Kwon
authors.forename: R
authors.initials: R
authors.lastname: Lin
authors.forename: L
authors.initials: L
authors.lastname: Petropoulos
mesh_terms: D000595:Amino Acid Sequence; D047390:Casein Kinase II; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D016356:Gene Products, tax / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins; D008954:Models, Biological; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D012190:Retroviridae / Q000502:physiology*; D015398:Signal Transduction; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D014764:Viral Proteins; D000072000:NF-KappaB Inhibitor alpha; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases