Letter abstract
Nature Cell Biology 8, 986 - 993 (2006)
Published online: 13 August 2006 | doi:10.1038/ncb1458
PIASy mediates NEMO sumoylation and NF-
B activation in response to genotoxic stress
Angela M. Mabb1, Shelly M. Wuerzberger-Davis1 & Shigeki Miyamoto1
Protein modification by SUMO (small ubiquitin-like modifier) is an important regulatory mechanism for multiple cellular processes1, 2. SUMO-1 modification of NEMO (NF-
B essential modulator), the IB kinase (IKK) regulatory subunit, is critical for activation of NF-B by genotoxic agents3. However, the SUMO ligase, and the mechanisms involved in NEMO sumoylation, remain unknown. Here, we demonstrate that although small interfering RNAs (siRNAs) against PIASy (protein inhibitor of activated STATy) inhibit NEMO sumoylation and NF-B activation in response to genotoxic agents, overexpression of PIASy enhances these events. PIASy preferentially stimulates site-selective modification of NEMO by SUMO-1, but not SUMO-2 and SUMO–3, in vitro. PIASy–NEMO interaction is increased by genotoxic stress and occurs in the nucleus in a manner mutually exclusive with IKK interaction. In addition, hydrogen peroxide (H2O2) also increases PIASy–NEMO interaction and NEMO sumoylation, whereas antioxidants prevent these events induced by DNA-damaging agents. Our findings demonstrate that PIASy is the first SUMO ligase for NEMO whose substrate specificity seems to be controlled by IKK interaction, subcellular targeting and oxidative stress conditions.
- Program in Molecular and Cellular Pharmacology, Department of Pharmacology, University of Wisconsin, Madison, WI 53706, USA.
Correspondence to: Shigeki Miyamoto1 e-mail: smiyamot@wisc.edu
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