title: Smurf1 protein negatively regulates interferon-γ signaling through promoting STAT1 protein ubiquitination and degradation.
abstract: Interferons are important cytokines that mediate antiviral, antiproliferative, antitumor, and immunoregulatory activities. However, uncontrolled IFN signaling may lead to autoimmune diseases. Here we identified Smurf1 as a negative regulator for IFN-γ signaling by targeting STAT1 for ubiquitination and proteasomal degradation. Smurf1 interacted with STAT1 through the WW domains of Smurf1 and the PY motif in STAT1 and catalyzed K48-linked polyubiquitination of STAT1. Interestingly, the Smurf1-mediated ubiquitination and degradation did not require STAT1 tyrosine and serine phosphorylation. Subsequently, overexpression of Smurf1 attenuated IFN-γ-mediated STAT1 activation and antiviral immune responses, whereas knockdown of Smurf1 enhanced IFN-γ-mediated STAT1 activation, expression of STAT1 target genes, and antiviral immune responses. Furthermore, IFN-γ stimulation led to enhanced expression of Smurf1. Therefore, our results demonstrate that Smurf1 is a negative feedback regulator for IFN-γ signaling by targeting STAT1 for ubiquitination and proteasomal degradation.
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Immunology, Shandong University Medical School, Jinan, Shandong 250012, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Immunology, Shandong University Medical School, Jinan, Shandong 250012, China.
authors.forename: Jianni
authors.initials: J
authors.lastname: Qi
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Immunology, Shandong University Medical School, Jinan, Shandong 250012, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Immunology, Shandong University Medical School, Jinan, Shandong 250012, China. Electronic address: cgao@sdu.edu.cn.
authors.forename: Chengjiang
authors.initials: C
authors.lastname: Gao
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D014777:Virus Diseases / Q000276:immunology / Q000378:metabolism
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; C498342:SMURF1 protein, human; C492381:Smurf1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex