Tyrosine phosphorylation of the E 3 ubiquitin ligase TRIM 21 positively regulates interaction with IRF 3 and hence TRIM 21 activity

semanticscholar(2015)

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摘要
Patients suffering from Systemic Lupus Erythematous (SLE) have elevated type I interferon (IFN) levels which correlate with disease activity and severity. TRIM21, an autoantigen associated with SLE, has been identified as an ubiquitin E3 ligase that targets the transcription factor IRF3 in order to turn off and limit type I IFN production following detection of viral and bacterial infection by Toll Like Receptors (TLRs). However, how the activity of TRIM21 is regulated downstream of TLRs is unknown. In this study we demonstrate that TRIM21 is tyrosine phosphorylated following TLR3 and TLR4 stimulation, suggesting that its activity is potentially regulated by tyrosine phosphorylation. Using Netphos, we have identified three key tyrosines that are strongly predicted to be phosphorylated, two of which are conserved between the human and murine forms of TRIM21, at residues 343, 388, and 393, all of which have been mutated from tyrosine to phenylalanine (Y343F, Y388F, and Y393F). We have observed that tyrosine phosphorylation of TRIM21 only occurs in the substrate binding PRY/ SPRY domain, and that Y393, and to a lesser extent, Y388 are required for TRIM21 to function as a negative regulator of IFNb promoter activity. Further studies revealed that mutating Y393 to phenylalanine inhibits the ability of TRIM21 to interact with its substrate, IRF3, thus providing a molecular explanation for the lack of activity of Y393 on the IFN-b promoter. Our data demonstrates a novel role for tyrosine phosphorylation in regulating the activity of TRIM21 downstream of TLR3 and TLR4. Given the pathogenic role of TRIM21 in systemic autoimmunity, these findings have important implications for the development of novel therapeutics. Citation: Stacey KB, Breen E, Jefferies CA (2012) Tyrosine Phosphorylation of the E3 Ubiquitin L gase TRIM21 Positively Regulates Interaction with IRF3 and Hence TRIM21 Activity. PLoS ONE 7(3): e34041. doi:10.1371/journal.pone.0034041 Editor: George C. Tsokos, Beth Israel Deaconess Medical Center, United States of America Received November 15, 2011; Accepted February 21, 2012; Published March 30, 2012 Copyright: 2012 Stacey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by funding from Science Foundation Ireland under grant no. [05/PICA/B815] and [08/IN.1/B2091], through the National Biophotonics and Imaging Platform, Ireland (NBIP), and funded by the Irish Government’s Programme for Research in Third Level Institutions, Cycle 4, Ireland’s EU Structural Funds Programmes 2007–2013, Grant no. [1101Q], and from the Alliance Lupus Research (ALR) under the TIL program [proposal number 187805]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: cjefferies@rcsi.ie
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