title: PIASy inhibits virus-induced and interferon-stimulated transcription through distinct mechanisms.
abstract: The protein inhibitor of activated STAT (PIAS) family proteins regulates innate immune responses by controlling transcription induced by Toll-like receptor, RIG-I-like receptor signaling, and JAK/STAT pathways. Here, we show that PIASy negatively regulates type I interferon (IFN) transcription. Virus infection led to enhanced type I IFN induction in PIASy null cells, and conversely PIASy overexpression reduced IFN transcription. A mutation in the LXXLL motif of the SAP domain abolished inhibition of IFN-stimulated gene expression but did not affect virus or Toll-like receptor/RIG-I-like receptor-stimulated IFN transcription, indicating that PIASy employs distinct mechanisms to inhibit virus-induced and IFN-stimulated transcription. SUMO E3 activity was not required for PIASy inhibition of IFN transcription; however, PIASy relied on the SUMO modification mechanism to inhibit IFN transcription, because the activity of the SUMO-interacting motif was required for inhibition, and knockdown of SUMO E2 enzyme UBC9 decreased inhibitory activity of PIASy. Our results demonstrate that PIASy negatively regulates both IFN transcription and IFN-stimulated gene expression through multiple mechanisms utilizing the function of different domains.
authors.affiliation: From the Departments of Virology III and. Electronic address: kubota@nih.go.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, Tokyo 208-0011, Japan and.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Matsuoka
authors.affiliation: the Laboratory of Molecular Growth Regulation, Genomics of Differentiation Program, NICHD, National Institutes of Health, Bethesda, Maryland 20892-2753.
authors.forename: Songxiao
authors.initials: S
authors.lastname: Xu
authors.affiliation: From the Departments of Virology III and.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Otsuki
authors.affiliation: From the Departments of Virology III and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeda
authors.affiliation: From the Departments of Virology III and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.affiliation: the Laboratory of Molecular Growth Regulation, Genomics of Differentiation Program, NICHD, National Institutes of Health, Bethesda, Maryland 20892-2753.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058207:Sumoylation / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D000097905:Roundabout Proteins
chemical_list: D007371:Interferon-gamma; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050828:Protein Inhibitors of Activated STAT; D011956:Receptors, Cell Surface; D025842:SUMO-1 Protein; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9; C414349:Piasy protein, mouse; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins