Smurf1 negatively regulates interferon-γ signaling through promoting STAT1 ubiquitination and degradation.

Interferons are important cytokines that mediate anti-viral, anti-proliferative, anti-tumor and immuno-regulatory activities. But, uncontrolled IFN signaling may lead to autoimmune diseases. Here we identified Smurf1 as a negative regulator for IFN-gamma signaling by targeting STAT1 for unbiquitination and proteasomal degradation. Smurf1 interacted with STAT1 through the WW domains of Smurf1 ...
and the PY motif in STAT1, and catalyzed K48-linked polyubiquitination of STAT1. Interestingly, the Smurf1-mediated ubiquitination and degradation did not require STAT1 tyrosine and serine phosphorylation. Subsequently, overexpression of Smurf1 attenuated IFN-gamma-mediated STAT1 activation and anti-viral immune responses, while knockdown of Smurf1 enhanced IFN-gamma-mediated STAT1 activation, expression of STAT1 target genes and anti-viral immune responses. Furthermore, IFN-gamma stimulation led to enhanced expression of Smurf1. Therefore, our results demonstrate that Smurf1 is a negative feedback regulator for IFN-gamma signaling by targeting STAT1 for ubiquitination and proteasomal degradation.
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Date: Apr. 02, 2012
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