title: Interactome disassembly during apoptosis occurs independent of caspase cleavage.
abstract: Protein-protein interaction networks (interactomes) define the functionality of all biological systems. In apoptosis, proteolysis by caspases is thought to initiate disassembly of protein complexes and cell death. Here we used a quantitative proteomics approach, protein correlation profiling (PCP), to explore changes in cytoplasmic and mitochondrial interactomes in response to apoptosis initiation as a function of caspase activity. We measured the response to initiation of Fas-mediated apoptosis in 17,991 interactions among 2,779 proteins, comprising the largest dynamic interactome to date. The majority of interactions were unaffected early in apoptosis, but multiple complexes containing known caspase targets were disassembled. Nonetheless, proteome-wide analysis of proteolytic processing by terminal amine isotopic labeling of substrates (TAILS) revealed little correlation between proteolytic and interactome changes. Our findings show that, in apoptosis, significant interactome alterations occur before and independently of caspase activity. Thus, apoptosis initiation includes a tight program of interactome rearrangement, leading to disassembly of relatively few, select complexes. These early interactome alterations occur independently of cleavage of these protein by caspases.
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.|Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Nichollas E
authors.initials: NE
authors.lastname: Scott
authors.affiliation: Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Lindsay D
authors.initials: LD
authors.lastname: Rogers
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.|Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Prudova
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.|Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Nat F
authors.initials: NF
authors.lastname: Brown
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.|Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Fortelny
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.|Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada foster@chibi.ubc.ca.|Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Leonard J
authors.identifier: 0000-0001-8551-4817
authors.initials: LJ
authors.lastname: Foster
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002853:Chromatography, Liquid; D003593:Cytoplasm / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling; D019169:Jurkat Cells; D013058:Mass Spectrometry; D008928:Mitochondria / Q000378:metabolism*; D060066:Protein Interaction Maps; D059748:Proteolysis; D040901:Proteomics / Q000379:methods*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor; D020169:Caspases
keywords: SILAC; caspase; protein complexes; protein correlation profiling