The SARS coronavirus papain like protease can inhibit IRF3 at a post activation step that requires deubiquitination activity

Virology Journal

Matthew Frieman¹  Alissa Pham²  Alexandra Schäfer³  Krystal Matthews¹ 

[1] Department of Microbiology and Immunology, University of Maryland at Baltimore, 685 West Baltimore St., Room 380, Baltimore 21201, MD, USA;Current Address: NYU Langone Medical Center, Department of Pathology, 538 Medical Science Building, New York 10016, NY, USA;Department of Epidemiology, University of North Carolina, 3304 Michael Hooker Research Building, Chapel Hill 27599, NC, USA

关键词: Innate immunity;    Interferon;    IRF3;    Severe acute respiratory syndrome;    Coronavirus;   

Others  :  1131073
DOI  :  10.1186/s12985-014-0209-9

 received in 2014-08-29, accepted in 2014-11-18,  发布年份 2014

【 摘 要 】

Background

The outcome of a viral infection is regulated by complex interactions of viral and host factors. SARS coronavirus (SARS-CoV) engages and regulates several innate immune response pathways during infection. We have previously shown that the SARS-CoV Papain-like Protease (PLpro) inhibits type I interferon (IFN) by inhibiting IRF3 phosphorylation thereby blocking downstream Interferon induction. This finding prompted us to identify other potential mechanisms of inhibition of PLpro on IFN induction.

Methods

We have used plasmids expressing PLpro and IRF3 including an IRF3 mutant that is constitutively active, called IRF3(5D). In these experiments we utilize transfections, chromatin immunoprecipitation, Electro-mobility Shift Assays (EMSA) and protein localization to identify where IRF3 and IRF3(5D) are inhibited by PLpro.

Results

Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response.

Conclusion

These results demonstrate an additional mechanism that PLpro is able to inhibit IRF3 signaling. These data suggest novel innate immune antagonism activities of PLpro that may contribute to SARS-CoV pathogenesis.

【 授权许可】

   
2014 Matthews et al.; licensee BioMed Central Ltd.

【 图 表 】

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