Institute of Molecular Biology of Plants, Strasbourg
“Human DICER helicase domain recruits PKR and modulates its antiviral activity”
Plos Pathogen https://doi.org/10.1371/journal.ppat.1009549
Thomas C. Montavon, Morgane Baldaccini, Mathieu Lefèvre, Erika Girardi, Béatrice Chane-Woon-Ming, Mélanie Messmer, Philippe Hammann, Johana Chicher and Sébastien Pfeffer.
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Thomas Montavon, 34, completed his thesis in Strasbourg at the Institute of Molecular Biology of Plants in the team of Dr Patrice DUNOYER. During his doctoral studies, he was mainly interested in the biogenesis of endogenous siRNAs in the model plant Arabidopsis Thaliana. He then obtained a post-doctoral position in the laboratory of Dr Sébastien PFEFFER at the Institute of Molecular and Cellular Biology and studied the role of RNA interference in the antiviral response in human cells. While RNAi has been recognized as an efficient antiviral defense system in plants and insects, its physiological importance in mammals remains to be determined. Using mass spectrometry analysis, Thomas Montavon and his collaborators determined the interactome of DICER in human cells and showed that PKR is specifically enriched during infection with the Sindbis virus or the Semliki forest virus. The N-terminal helicase domain of the DICER protein acts as a platform to recruit these factors during infection and prevents PKR from being fully active. These study unveiled a new role for DICER in regulating the cellular response to viral infection.
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Summury of the article
The antiviral innate immune response mainly involves type I interferon (IFN) in mammalian cells. The contribution of the RNA silencing machinery remains to be established, but several recent studies indicate that the ribonuclease DICER can generate viral siRNAs in specific conditions. It has also been proposed that type I IFN and RNA silencing could be mutually exclusive antiviral responses. In order to decipher the implication of DICER during infection of human cells with alphaviruses such as the Sindbis virus and Semliki forest virus, we determined its interactome by proteomics analysis. We show that DICER specifically interacts with several double-stranded RNA binding proteins and RNA helicases during viral infection. In particular, proteins such as DHX9, ADAR-1 and the protein kinase RNA-activated (PKR) are enriched with DICER in virus-infected cells. We demonstrate that the helicase domain of DICER is essential for this interaction and that its deletion confers antiviral properties to this protein in an RNAi-independent, PKR-dependent, manner.
