Innate Immunity and Viral Infection

Among the central aspects of our laboratory’s work has been to investigate mRNA translational control during viral infection. We documented the breakthrough discovery of cap-independent translation initiation through the internal ribosome entry site (IRES) on poliovirus mRNA, thereby challenging the dogma that ribosomes could only bind to eukaryotic mRNAs through the 5' end.

This discovery prompted extensive research, which ultimately revealed the functional role of IRESes in viruses like poliovirus and HCV and in cellular mRNAs that encode proteins with significant functions in inflammation, apoptosis, and growth control. Subsequent work by our lab showed that the cleavage of both eIF4GI and eIF4GII (called today eIF4G1 and eIF4G3, the scaffolding protein of the eIF4F complex) is required to shut down host protein synthesis during poliovirus infection. We also showed that the secondary structure of HIV TAR mRNA could activate the double-stranded RNA activated protein kinase (PKR). Subsequently, it was discovered that other mRNAs exhibit such capability, which greatly advanced the understanding of the interferon response in virus-infected cells.

We recently discovered that 4EHP/GIGYF2 suppresses interferon-β (IFN-β) production in virus-infected cells via miR-34a-induced translational silencing of the Ifnb1 mRNA. This mechanism is an adaptive response to inflammation to prevent exacerbated cytokine levels that could engender auto-immune disease. However, this function positions 4EHP as an ideal evolutionarily adaptive target for viruses to evade innate immunity. Consistent with this notion, we discovered that the SARS-CoV-2 non-structural protein NSP2 directly interacts with GIGYF2 to enhance the binding of the latter to 4EHP, thereby further promoting the repression of Ifnb1 mRNA translation and IFN-β production.

4EHP suppresses IFN-β production by effecting the miR-34a-induced translational silencing of Ifnb1 mRNA (Zhang et al. Molecular Cell 2021)

Selected Papers

  1. Zhang Xu, Jung-Hyun Choi, David L. Dai, Jun Luo, Reese Jalal Ladak, Qian Li, Yimeng Wang, Christine Zhang, Shane Wiebe, Alex C. H. Liu, Xiaozhuo Ran, Jiaqi Yang, Parisa Naeli, Aitor Garzia, Lele Zhou, Niaz Mahmood, Qiyun Deng, Mohamed Elaish, Rongtuan Lin, Lara K. Mahal , Tom C. Hobman, Jerry Pelletier, Tommy Alain, Silvia M. Vidal, Thomas Duchaine, Mohammad T. Mazhab-Jafari, Xiaojuan Mao, Seyed Mehdi Jafarnejad, Nahum Sonenberg (2022). SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation. PNAS. doi: 10.1073/pnas.2204539119

  2. Xu Zhang, Clément Chapat, Peng Wang, Jung-Hyun Choi, Qian Li, Jun Luo, Shane Wiebe, Sung-Hoon Kim, Nathaniel Robichaud, Isabela Fabri Karam, David Dai, Angela P Hackett, Rongtuan Lin, Tommy Alain, Long Yang, Seyed Mehdi Jafarnejad, Nahum Sonenberg (2021). microRNA-induced translational control of antiviral immunity by the cap-binding protein 4EHP. Molecular Cell. doi: 10.1016/j.molcel.2021.01.030

  3. Barbara Herdy, Maritza Jaramillo, Yuri V Svitkin, Amy B Rosenfeld, Mariko Kobayashi, Derek Walsh, Tommy Alain, Polen Sean, Nathaniel Robichaud, Ivan Topisirovic, Luc Furic, Ryan J O Dowling, Annie Sylvestre, Liwei Rong, Rodney Colina, Mauro Costa-Mattioli, Jörg H Fritz, Martin Olivier, Earl Brown, Ian Mohr, Nahum Sonenberg (2012). Translational control of the activation of transcription factor NF-κB and production of type I interferon by phosphorylation of the translation factor eIF4E. Nature Immunology. doi: 10.1038/ni.2291

  4. Rodney Colina, Mauro Costa-Mattioli, Ryan J O Dowling, Maritza Jaramillo, Lee-Hwa Tai, Caroline J Breitbach, Yvan Martineau, Ola Larsson, Liwei Rong, Yuri V Svitkin, Andrew P Makrigiannis, John C Bell, Nahum Sonenberg (2008). Translational control of the innate immune response through IRF-7. Nature. doi: 10.1038/nature06730

  5. Jerry Pelletier, Nahum Sonenberg (1988). Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature. doi: 10.1038/334320a0