title: ISG15 deregulates autophagy in genotoxin-treated ataxia telangiectasia cells.
abstract: Ataxia-telangiectasia (A-T) is a cerebellar neurodegenerative disorder; however, the basis for the neurodegeneration in A-T is not well established. Lesions in the ubiquitin and autophagy pathways are speculated to contribute to the neurodegeneration in other neurological diseases and may have a role in A-T neurodegeneration. Our recent studies revealed that the constitutively elevated ISG15 pathway impairs targeted proteasome-mediated protein degradation in A-T cells. Here, we demonstrate that the basal autophagy pathway is activated in the ubiquitin pathway-compromised A-T cells. We also show that genotoxic stress triggers aberrant degradation of the proteasome and autophagy substrates (autophagic flux) in A-T cells. Inhibition of autophagy at an early stage using 3-methyladenine blocked UV-induced autophagic flux in A-T cells. On the other hand, bafilomycin A1, which inhibits autophagy at a late stage, failed to block UV-induced autophagic flux, suggesting that overinduction of autophagy may underlie aberrant autophagic flux in A-T cells. The ISG15-specific shRNA that restored proteasome function restores autophagic function in A-T cells. These findings suggest that autophagy compensates for the ISG15-dependent ablation of proteasome-mediated protein degradation in A-T cells. Genotoxic stress overactivates this compensatory mechanism, triggering aberrant autophagic flux in A-T cells. Supporting the model, we show that autophagy is activated in the brain tissues of human A-T patients. This highlights a plausible causal contribution of a novel "ISG15 proteinopathy" in A-T neuronal cell death.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center School of Medicine, New Orleans, Louisiana 70112, USA.
authors.forename: Shyamal D
authors.initials: SD
authors.lastname: Desai
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Reed
authors.forename: Shilka
authors.initials: S
authors.lastname: Babu
authors.forename: Eric A
authors.initials: EA
authors.lastname: Lorio
mesh_terms: D001259:Ataxia / Q000378:metabolism; D001260:Ataxia Telangiectasia / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics* / Q000502:physiology; D001921:Brain / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007372:Interferons / Q000378:metabolism; D016086:Lentivirus / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence / Q000379:methods; D009153:Mutagens / Q000737:chemistry; D019636:Neurodegenerative Diseases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D016207:Cytokines; D009153:Mutagens; D034741:RNA, Small Interfering; D014452:Ubiquitins; C074034:ISG15 protein, human; D007372:Interferons; D046988:Proteasome Endopeptidase Complex