Ubiquitin-specific protease 13 regulates IFN signaling by stabilizing STAT1.
The IFN immune system comprises type I, II, and III IFNs, signals through the JAK-STAT pathway, and plays central roles in host defense against viral infection. Posttranslational modifications such as ubiquitination regulate diverse molecules in the IFN pathway. To search for the deubiquitinating enzymes (DUBs) involved in the antiviral activity of IFN, we used RNA interference screening to identify a human DUB, ubiquitin-specific protease (USP) 13, whose expression modulates the antiviral activity of IFN-α against dengue virus serotype 2 (DEN-2). The signaling events and anti-DEN-2 activities of IFN-α and IFN-γ were reduced in cells with USP13 knockdown but enhanced with USP13 overexpression. USP13 may regulate STAT1 protein because the protein level and stability of STAT1 were increased with USP13 overexpression. Furthermore, STAT1 ubiquitination was reduced in cells with USP13 overexpression and increased with USP13 knockdown regardless of with or without IFN-α treatment. Thus, USP13 positively regulates type I and type II IFN signaling by deubiquitinating and stabilizing STAT1 protein. Overall, to our knowledge, USP13 is the first DUB identified to modulate STAT1 and play a role in the antiviral activity of IFN against DEN-2 replication.
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
Hom-Ming
HM
Yeh
Chia-Yi
CY
Yu
Ho-Chun
HC
Yang
Shih-Han
SH
Ko
Ching-Len
CL
Liao
Yi-Ling
YL
Lin
D015153:Blotting, Western; D003716:Dengue Virus / Q000276:immunology*; D010450:Endopeptidases / Q000276:immunology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D007372:Interferons / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D064570:Ubiquitin-Specific Proteases
D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007372:Interferons; D010450:Endopeptidases; C561638:USP13 protein, human; D064570:Ubiquitin-Specific Proteases