title: A novel role for ATM in regulating proteasome-mediated protein degradation through suppression of the ISG15 conjugation pathway.
abstract: Ataxia Telangiectasia (A-T) is an inherited immunodeficiency disorder wherein mutation of the ATM kinase is responsible for the A-T pathogenesis. Although the precise role of ATM in A-T pathogenesis is still unclear, its function in responding to DNA damage has been well established. Here we demonstrate that in addition to its role in DNA repair, ATM also regulates proteasome-mediated protein turnover through suppression of the ISG15 pathway. This conclusion is based on three major pieces of evidence: First, we demonstrate that proteasome-mediated protein degradation is impaired in A-T cells. Second, we show that the reduced protein turnover is causally linked to the elevated expression of the ubiquitin-like protein ISG15 in A-T cells. Third, we show that expression of the ISG15 is elevated in A-T cells derived from various A-T patients, as well as in brain tissues derived from the ATM knockout mice and A-T patients, suggesting that ATM negatively regulates the ISG15 pathway. Our current findings suggest for the first time that proteasome-mediated protein degradation is impaired in A-T cells due to elevated expression of the ISG15 conjugation pathway, which could contribute to progressive neurodegeneration in A-T patients.
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Wood
authors.forename: Surendran
authors.initials: S
authors.lastname: Sankar
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Reed
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Haas
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: McKinnon
authors.forename: Shyamal D
authors.initials: SD
authors.lastname: Desai
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000378:metabolism / Q000473:pathology*; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D014452:Ubiquitins / Q000032:analysis*; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C489550:G1p2 protein, mouse; D011506:Proteins; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C074034:ISG15 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex