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Crucial Role of the Amino-Terminal Tyrosine Residue 42 and the Carboxyl-Terminal PEST Domain of IB in NF-B Activation by an Oxidative Stress¹

Sonia Schoonbroodt^*, Valérie Ferreira, Martin Best-Belpomme, Johan R. Boelaert^§, Sylvie Legrand-Poels^*, Marie Korner and Jacques Piette^2,*

^* Laboratory of Virology, Institute of Pathology, University of Liege, Liege, Belgium; Oncogenesis, Differentiation, and Signal Transduction Laboratory, Institut de Recherche sur le Cancer-Centre Nationale de la Recherche Scientifique, Villejuif, France; Institut National de la Santé et de la Recherche Médicale, Unit 99, Hôpital Henri Mondor, Creteil, France; and ^§ Unit of Infectious Diseases, AZ Sint-Jan, Brugge, Belgium

Activation of transcription factor NF-B involves the signal-dependent degradation of basally phosphorylated inhibitors such as IB. In response to proinflammatory cytokines or mitogens, the transduction machinery has recently been characterized, but the activation mechanism upon oxidative stress remains unknown. In the present work, we provide several lines of evidence that NF-B activation in a T lymphocytic cell line (EL4) by hydrogen peroxide (H₂O₂) did not involve phosphorylation of the serine residues 32 and 36 in the amino-terminal part of IB. Indeed, mutation of Ser³² and Ser³⁶ blocked IL-1ß- or PMA-induced NF-B activation, but had no effect on its activation by H₂O₂. Although IB was phosphorylated upon exposure to H₂O₂, tyrosine residue 42 and the C-terminal PEST (proline-glutamic acid-serine-threonine) domain played an important role. Indeed, mutation of tyrosine 42 or serine/threonine residues of the PEST domain abolished NF-B activation by H₂O₂, while it had no effect on activation by IL-1ß or PMA-ionomycin. This H₂O₂-inducible phosphorylation was not dependent on IB kinase activation, but could involve casein kinase II, because an inhibitor of this enzyme (5,6-dichloro-1-ß-D-ribofuranosyl-benzimidazole) blocks NF-B activation. H₂O₂-induced IB phosphorylation was followed by its degradation by calpain proteases or through the proteasome. Taken together, our findings suggest that NF-B activation by H₂O₂ involves a new mechanism that is totally distinct from those triggered by proinflammatory cytokines or mitogens.