title: Interferon-stimulated gene 15 (ISG15) and ISG15-linked proteins can associate with members of the selective autophagic process, histone deacetylase 6 (HDAC6) and SQSTM1/p62.
abstract: The ubiquitin-like interferon (IFN)-stimulated gene 15 (ISG15) and its specific E1, E2, and E3 enzymes are transcriptionally induced by type I IFNs. ISG15 conjugates newly synthesized proteins. ISG15 linkage to proteins appears to be an important downstream IFN signaling event that discriminates cellular and pathogenic proteins synthesized during IFN stimulation from existing proteins. This eliminates potentially pathogenic proteins as the cell attempts to return to normal homeostasis after IFN "stressed" conditions. However, the molecular events that occur in this process are not well known. Here, we show that the C-terminal LRLRGG of ISG15 interacts with the binder of ubiquitin zinc finger (BUZ) domain of histone deacetylase 6 (HDAC6). Because HDAC6 is involved in the autophagic clearance of ubiquitinated aggregates during which SQSTM1/p62 plays a major role as a cargo adapter, we also were able to confirm that p62 binds to ISG15 protein and its conjugated proteins upon forced expression. Both HDAC6 and p62 co-localized with ISG15 in an insoluble fraction of the cytosol, and this co-localization was magnified by the proteasome inhibitor MG132. In addition, ISG15 was degraded via the lysosome. Overexpression of ISG15, which leads to an increased conjugation level of the cellular proteome, enhanced autophagic degradation independently of IFN signaling transduction. These results thus indicate that ISG15 conjugation marks proteins for interaction with HDAC6 and p62 upon forced stressful conditions likely as a step toward autophagic clearance.
authors.affiliation: From the Harvey Cushing Neuro-oncology Laboratories, Harvard Institutes of Medicine, Department of Neurosurgery and Institute for the Neurosciences at the Brigham and Women's Hospital, Boston, Massachusetts 02115 and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: From the Harvey Cushing Neuro-oncology Laboratories, Harvard Institutes of Medicine, Department of Neurosurgery and Institute for the Neurosciences at the Brigham and Women's Hospital, Boston, Massachusetts 02115 and.
authors.forename: Tran
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219.
authors.forename: William F
authors.initials: WF
authors.lastname: Goins
authors.affiliation: From the Harvey Cushing Neuro-oncology Laboratories, Harvard Institutes of Medicine, Department of Neurosurgery and Institute for the Neurosciences at the Brigham and Women's Hospital, Boston, Massachusetts 02115 and EAChiocca@partners.org.
authors.forename: Ennio Antonio
authors.initials: EA
authors.lastname: Chiocca
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001343:Autophagy; D016207:Cytokines / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004318:Doxycycline / Q000737:chemistry; D057809:HEK293 Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate; D007976:Leupeptins / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D061988:Proteasome Inhibitors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D018076:DNA, Complementary; D007976:Leupeptins; D061988:Proteasome Inhibitors; D020543:Proteome; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014452:Ubiquitins; C074034:ISG15 protein, human; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D004318:Doxycycline; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Autophagy; Histone Deacetylase 6 (HDAC6); ISG15; Infection; Lysosome; Post-translational Modification (PTM); SQSTM1; Ubiquitin; Virus; p62