title: Comparative proteomics analysis reveals roles for FADD in the regulation of energy metabolism and proteolysis pathway in mouse embryonic fibroblast.
abstract: Fas-associated death domain-containing protein (FADD) is a classical apoptotic pathway adaptor. Further studies revealed that it also plays essential roles in nonapoptotic processes, which is assumed to be regulated by its phosphorylation. However, the exact mechanisms are still poorly understood. To study the nonapoptotic effects of FADD, a comprehensive strategy of proteomics identification combined with bioinformatic analysis was undertaken to identify proteins differentially expressed in three cell lines containing FADD and its mutant, FADD-A and FADD-D. The cell lines were thought to bear wild-type FADD, unphosphorylated FADD mimic and constitutive phosphorylated FADD mimic, respectively. A total of 47 proteins were identified to be significantly changed due to FADD phosphorylation. Network analysis using MetaCore™ identified a number of changed proteins that were involved in cellular metabolic process, including lipid metabolism, fatty acid metabolism, glycolysis, and oxidative phosphorylation. The finding that FADD-D cell line showed an increase in fatty acid oxidation argues that it could contribute to the leaner phenotype of FADD-D mice as reported previously. In addition, six proteins related to the ubiquitin-proteasome pathway were also specifically overexpressed in FADD-D cell line. Finally, the c-Myc gene represents a convergent hub lying at the center of dysregulated pathways, and was upregulated in FADD-D cells. Taken together, these studies allowed us to conclude that impaired mitochondrial function and proteolysis might play pivotal roles in the dysfunction associated with FADD phosphorylation-induced disorders.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, PR China.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Zhuang
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Gan
authors.forename: Weiwei
authors.initials: W
authors.lastname: Jiang
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Zi-Chun
authors.initials: ZC
authors.lastname: Hua
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D015180:Electrophoresis, Gel, Two-Dimensional; D004734:Energy Metabolism; D053200:Fas-Associated Death Domain Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D010766:Phosphorylation; D060066:Protein Interaction Maps; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein
keywords: Cell biology; Energy metabolism; FADD; Fatty acid oxidation; Proteolysis; Two-dimensional electrophoresis