Structure-function analysis indicates that sumoylation modulates DNA-binding activity of STAT1
Grönholm, Juha; Vanhatupa, Sari; Ungureanu, Daniela; Väliaho, Jouni; Laitinen, Tuomo; Valjakka, Jarkko; Silvennoinen, Olli (2012)
2012
BMC Biochemistry 13
20
Biolääketieteellisen teknologian yksikkö - Institute of Biomedical Technology
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Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:uta-201301041002
https://urn.fi/URN:NBN:fi:uta-201301041002
Kuvaus
BioMed Central open access
Tiivistelmä
Background
STAT1 is an essential transcription factor for interferon-γ-mediated gene responses. A distinct sumoylation consensus site (ψKxE) 702IKTE705 is localized in the C-terminal region of STAT1, where Lys703 is a target for PIAS-induced SUMO modification. Several studies indicate that sumoylation has an inhibitory role on STAT1-mediated gene expression but the molecular mechanisms are not fully understood.
Results
Here, we have performed a structural and functional analysis of sumoylation in STAT1. We show that deconjugation of SUMO by SENP1 enhances the transcriptional activity of STAT1, confirming a negative regulatory effect of sumoylation on STAT1 activity. Inspection of molecular model indicated that consensus site is well exposed to SUMO-conjugation in STAT1 homodimer and that the conjugated SUMO moiety is directed towards DNA, thus able to form a sterical hindrance affecting promoter binding of dimeric STAT1. In addition, oligoprecipitation experiments indicated that sumoylation deficient STAT1 E705Q mutant has higher DNA-binding activity on STAT1 responsive gene promoters than wild-type STAT1. Furthermore, sumoylation deficient STAT1 E705Q mutant displayed enhanced histone H4 acetylation on interferon-γ-responsive promoter compared to wild-type STAT1.
Conclusions
Our results suggest that sumoylation participates in regulation of STAT1 responses by modulating DNA-binding properties of STAT1.
Keywords:
Signal transduction; Transcription factors; Sumoylation; Signal transducers and activators of transcription (STATs); Interferon
STAT1 is an essential transcription factor for interferon-γ-mediated gene responses. A distinct sumoylation consensus site (ψKxE) 702IKTE705 is localized in the C-terminal region of STAT1, where Lys703 is a target for PIAS-induced SUMO modification. Several studies indicate that sumoylation has an inhibitory role on STAT1-mediated gene expression but the molecular mechanisms are not fully understood.
Results
Here, we have performed a structural and functional analysis of sumoylation in STAT1. We show that deconjugation of SUMO by SENP1 enhances the transcriptional activity of STAT1, confirming a negative regulatory effect of sumoylation on STAT1 activity. Inspection of molecular model indicated that consensus site is well exposed to SUMO-conjugation in STAT1 homodimer and that the conjugated SUMO moiety is directed towards DNA, thus able to form a sterical hindrance affecting promoter binding of dimeric STAT1. In addition, oligoprecipitation experiments indicated that sumoylation deficient STAT1 E705Q mutant has higher DNA-binding activity on STAT1 responsive gene promoters than wild-type STAT1. Furthermore, sumoylation deficient STAT1 E705Q mutant displayed enhanced histone H4 acetylation on interferon-γ-responsive promoter compared to wild-type STAT1.
Conclusions
Our results suggest that sumoylation participates in regulation of STAT1 responses by modulating DNA-binding properties of STAT1.
Keywords:
Signal transduction; Transcription factors; Sumoylation; Signal transducers and activators of transcription (STATs); Interferon
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