Activation of the ubiquitin proteolytic system in murine acquired immunodeficiency syndrome affects IκBα turnover

Murine acquired immunodeficiency syndrome (MAIDS) is a complex immunopathology caused by a defective murine leukemia virus (LP-BM5) that mainly targets 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. (1997) Eur. J. Biochem. 247, 91-97]. In this report, He demonstrate that increased 26S proteasome activity is responsible for accelerated turnover of the I kappa B alpha inhibitor in lymph node extracts derived from animals with MAIDS. The molecular mechanisms mediating I kappa B alpha proteolysis involved constitutive phosphorylation of I kappa B alpha at Ser32 and Ser36 and subsequent ubiquitination, suggesting persistent activation of an NF-kappa B inducing pathway. Interestingly, enhanced I kappa B alpha degradation did 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 system may affect multiple immunoregulatory pathways and may in part explain the mechanisms leading to the profound immune dysregulation involved in MAIDS pathogenesis.