Activation of the ubiquitin proteolytic system in murine acquired immunodeficiency syndrome affects I kappa B alpha turnover

Murine acquired immunodeficiency syndrome (MAIDS) is a complex immunopathol ogy caused by a defective murine leukemia virus (LP-BM5) that mainly target s B-lymphocytes. Lymphadenophathy, splenomegaly, hypergammaglobulinemia and progressive immunodeficiency are prominent features of MAIDS. Previously, we showed that the ubiquitin proteolytic system was upregulated in infected lymph nodes [Crinelli, R., Fraternale, A., Casabianca, A. & Magnani, M. (1 997) Eur. J. Biochem. 247, 91-97]. In this report, He demonstrate that incr eased 26S proteasome activity is responsible for accelerated turnover of th e I kappa B alpha inhibitor in lymph node extracts derived from animals wit h MAIDS. The molecular mechanisms mediating I kappa B alpha proteolysis inv olved constitutive phosphorylation of I kappa B alpha at Ser32 and Ser36 an d subsequent ubiquitination, suggesting persistent activation of an NF-kapp a B inducing pathway. Interestingly, enhanced I kappa B alpha degradation d id not result in enhanced NF-kappa B DNA binding activity, but rather in a different subunit composition. The modulation of NF-kappa B/I kappa B syste m may affect multiple immunoregulatory pathways and may in part explain the mechanisms leading to the profound immune dysregulation involved in MAIDS pathogenesis.