title: Quantitative dissection and modeling of the NF-κB p100-p105 module reveals interdependent precursor proteolysis.
abstract: The mechanisms that govern proteolytic maturation or complete destruction of the precursor proteins p100 and p105 are fundamental to homeostasis and activation of NF-κB; however, they remain poorly understood. Using mass-spectrometry-based quantitative analysis of noncanonical LTβR-induced signaling, we demonstrate that stimulation induces simultaneous processing of both p100 and p105. The precursors not only form hetero-oligomers but also interact with the ATPase VCP/p97, and their induced proteolysis strictly depends on the signal response domain (SRD) of p100, suggesting that the SRD-targeting proteolytic machinery acts in cis and in trans. Separation of cellular pools by isotope labeling revealed synchronous dynamics of p105 and p100 proteolysis. The generation of p50 and p52 from their precursors depends on functional VCP/p97. We have developed quantitative mathematical models that describe the dynamics of the system and predict that p100-p105 complexes are signal responsive.
authors.affiliation: Signal Transduction Laboratory, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. Electronic address: yilmaz@mdc-berlin.de.
authors.forename: Zekiye Buket
authors.initials: ZB
authors.lastname: Yılmaz
authors.affiliation: Mathematical Modeling Group, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Bente
authors.initials: B
authors.lastname: Kofahl
authors.affiliation: Signal Transduction Laboratory, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany; Mass Spectrometry Group, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Beaudette
authors.affiliation: Mathematical Modeling Group, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Baum
authors.affiliation: Signal Transduction Laboratory, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Inbal
authors.initials: I
authors.lastname: Ipenberg
authors.affiliation: Leibniz-Institute for Age Research-Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Weih
authors.affiliation: Mathematical Modeling Group, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Mass Spectrometry Group, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Dittmar
authors.affiliation: Signal Transduction Laboratory, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. Electronic address: scheidereit@mdc-berlin.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Scheidereit
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D053259:Lymphotoxin beta Receptor; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D011498:Protein Precursors; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse