Proteolytic processing of NF-kappa B/I kappa B in human monocytes. ATP-dependent induction by pro-inflammatory mediators.
Proteolytic processing of select constituents of the nuclear factor kappa B (NF-kappa B)/inhibitor kappa B alpha (I kappa B) transcription factor system plays an important role in regulating the biological responses of monocytes to pro-inflammatory mediators. Nuclear translocation of NF-kappa B is preceded by the proteolytic degradation of I kappa B alpha, an ankyrin motif-rich inhibitor that traps NF-kappa B in the cytoplasm. In addition, formation of cytoplasmic NF-kappa B/I kappa B alpha complexes in quiescent cells requires constitutive proteolytic processing of p105, another ankyrin motif-rich inhibitory protein from which the p50 subunit of NF-kappa B is generated. We have demonstrated that, following stimulation of human monocytic cells with lipopolysaccharide or tumor necrosis factor-alpha, this critical p105 processing event is up-regulated in concert with the inactivation of I kappa B alpha. Moreover, the degradative loss of both p105 and I kappa B alpha is prevented in cells depleted of intracellular ATP. In activated monocytes, however, I kappa B alpha degradation occurs more rapidly than p105 processing to p50. Together these findings provide direct biochemical evidence that p105 and I kappa B alpha are differentially sensitive targets for inducible proteolysis via ATP-dependent degradative pathways.
Donald
R
R
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Ballard
D W
DW
Hawiger
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism*; D002460:Cell Line; D016521:Electrophoresis, Gel, Pulsed-Field; D006801:Humans; D006868:Hydrolysis; D018836:Inflammation Mediators / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051841:Transcription Factor RelB; D014157:Transcription Factors
D018836:Inflammation Mediators; D016328:NF-kappa B; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D014157:Transcription Factors; D051841:Transcription Factor RelB; D000255:Adenosine Triphosphate