Promyelocytic Leukemia Protein Isoform II Promotes Transcription Factor Recruitment To Activate Interferon Beta and Interferon-Responsive Gene Expression.
To trigger type I interferon (IFN) responses, pattern recognition receptors activate signaling cascades that lead to transcription of IFN and IFN-stimulated genes (ISGs). The promyelocytic leukemia (PML) protein has been implicated in these responses, although its role has not been defined. Here, we show that PML isoform II (PML-II) is specifically required for efficient induction of IFN-β transcription and of numerous ISGs, acting at the point of transcriptional complex assembly on target gene promoters. PML-II associated with specific transcription factors NF-κB and STAT1, as well as the coactivator CREB-binding protein (CBP), to facilitate transcriptional complex formation. The absence of PML-II substantially reduced binding of these factors and IFN regulatory factor 3 (IRF3) to IFN-β or ISGs promoters and sharply reduced gene activation. The unique C-terminal domain of PML-II was essential for its activity, while the N-terminal RBCC motif common to all PML isoforms was dispensable. We propose a model in which PML-II contributes to the transcription of multiple genes via the association of its C-terminal domain with relevant transcription complexes, which promotes the stable assembly of these complexes at promoters/enhancers of target genes, and that in this way PML-II plays a significant role in the development of type I IFN responses.
School of Life Sciences, University of Warwick, Coventry, United Kingdom.
Yixiang
Y
Chen
School of Life Sciences, University of Warwick, Coventry, United Kingdom.
Jordan
J
Wright
School of Life Sciences, University of Warwick, Coventry, United Kingdom.
Xueqiong
X
Meng
School of Life Sciences, University of Warwick, Coventry, United Kingdom Keith.Leppard@warwick.ac.uk.
Keith N
KN
Leppard
D002460:Cell Line; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D016899:Interferon-beta