Open AccessActivation of the ubiquitin proteolytic system in murine acquired immunodeficiency syndrome affects IκBα turnover
Author(s) -
Crinelli Rita,
Bianchi Marzia,
Gentilini Lucia,
Magnani Mauro,
Hiscott John
Publication year - 1999
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.1999.00485.x
Subject(s) - proteolysis , ubiquitin , biology , downregulation and upregulation , proteasome , pathogenesis , immunodeficiency , immunodeficiency syndrome , hypergammaglobulinemia , ubiquitins , phosphorylation , protein subunit , immune system , immunology , microbiology and biotechnology , genetics , antibody , gene , biochemistry , enzyme , ubiquitin ligase
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, we demonstrate that increased 26S proteasome activity is responsible for accelerated turnover of the IκBα inhibitor in lymph node extracts derived from animals with MAIDS. The molecular mechanisms mediating IκBα proteolysis involved constitutive phosphorylation of IκBα at Ser32 and Ser36 and subsequent ubiquitination, suggesting persistent activation of an NF‐κB inducing pathway. Interestingly, enhanced IκBα degradation did not result in enhanced NF‐κB DNA binding activity, but rather in a different subunit composition. The modulation of NF‐κB/IκB system may affect multiple immunoregulatory pathways and may in part explain the mechanisms leading to the profound immune dysregulation involved in MAIDS pathogenesis.