Activation of the ubiquitin proteolytic system in murine acquired immunodeficiency syndrome affects IkappaBalpha 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, we demonstrate that increased 26S proteasome activity is responsible for accelerated turnover of the IkappaBalpha inhibitor in lymph node extracts derived from animals with MAIDS. The molecular mechanisms mediating IkappaBalpha proteolysis involved constitutive phosphorylation of IkappaBalpha at Ser32 and Ser36 and subsequent ubiquitination, suggesting persistent activation of an NF-kappaB inducing pathway. Interestingly, enhanced IkappaBalpha degradation did not result in enhanced NF-kappaB DNA binding activity, but rather in a different subunit composition. The modulation of NF-kappaB/IkappaB system may affect multiple immunoregulatory pathways and may in part explain the mechanisms leading to the profound immune dysregulation involved in MAIDS pathogenesis.
Crinelli
R
R
Instuto di Chimica Biologica 'G. Fornaini', University of Urbino, Italy.
Bianchi
M
M
Gentilini
L
L
Magnani
M
M
Hiscott
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism; D016183:Murine Acquired Immunodeficiency Syndrome / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014452:Ubiquitins; D000072000:NF-KappaB Inhibitor alpha; D000255:Adenosine Triphosphate; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex