title: Interaction of amyotrophic lateral sclerosis/frontotemporal lobar degeneration-associated fused-in-sarcoma with proteins involved in metabolic and protein degradation pathways.
abstract: Fused-in-sarcoma (FUS) is a nuclear protein linked to amyotrophic lateral sclerosis and frontotemporal dementia. Under pathologic conditions, FUS frequently is accumulated in cytosoplasm, but how this altered distribution affects the protein interaction pattern of FUS is unclear. Using dual-tag affinity purification and mass spectrometry, we compared the interactome of the wild-type FUS and the P525 L mutant, which causes juvenile amyotrophic lateral sclerosis with the most severe phenotypes. The mutant FUS retained the ability to bind proteins involved in RNA metabolism. We found significant increased binding of P525 L to many metabolic enzymes. Furthermore, we identified and confirmed some novel interactions between FUS and proteins involved in neurodegenerative diseases and/or ubiquitin proteasome pathway, such as VCP/p97, PSF, UBA 1, and 26S proteosome non-ATPase regulatory subunit 12 (PSMD12/Rpn5). Accordingly, we have observed significantly reduced ATP levels and increased accumulation of poly-ubiquitinated proteins in cells with FUS accumulation. Therefore, our study suggested new mechanisms whereby FUS accumulation leads to defective energy metabolism and protein degradation by directly interacting with key regulators in these pathways.
authors.affiliation: Institute of Neuroscience and Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience and Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, Shanghai, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Institute of Neuroscience and Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Institute of Neuroscience and Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, Shanghai, China. Electronic address: Jin.Xu@ion.ac.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology; D004734:Energy Metabolism / Q000235:genetics*; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000235:genetics* / Q000502:physiology*; D059748:Proteolysis; D012333:RNA, Messenger / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D050505:Mutant Proteins; D012333:RNA, Messenger; D034702:RNA-Binding Protein FUS; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: Amyotrophic lateral sclerosis (ALS); Frontotemporal dementia (FTD); Fused-in-sarcoma (FUS); Metabolic; Protein degradation; Valocin-containing protein (VCP)