Control of Protein Synthesis by the UPS Under Stress

Project SummaryFollowing its infection, SARS-CoV-2 utilizes cellular networks to enable its efficient replication. Key for its successin hijacking cellular systems of host cells lies in the takeover of the translational apparatus, whereby the virusrequires eukaryotic translation initiation complex 4F (eIF4F) activity. To this end, cap-dependent and eIF4F-driven viral genome RNA translation is essential for production of the viral proteins required for its replication.Notably, cancer cells rewire their RNA translational machinery, as often reflected by enhanced activity and/orexpression of eIF4F subunits leading to increased complex activity. Thus, SARS-CoV-2 and translationalperturbations in cancer may converge on cap-dependent translation and, in particular, on the eIF4F complex.Accordingly, a different degree of susceptibility to SARS-CoV-2 infection is expected in cancer cells based ontheir pre-rewiring of the RNA translation machinery. The underlying hypothesis of this proposal is that targetingcomponents of the eIF4F complex is expected to provide novel therapeutic modality for inhibition ofSARS-CoV-2 replication, while exerting anti-neoplastic effects across broad spectrum of cancers. To testthis, we will define the effectiveness of RNA translation modulators, we have developed, in attenuating SARS-CoV-2 effect on eIF4F activity in lung cancer cells susceptible to coronavirus infection. The effect of RNAtranslation modulators on SARS-CoV-2 infected lung cancer cells response to commonly used therapy will bealso assessed. This is anticipated to improve understanding of coronavirus biology in context of neoplasia andin long-term provide therapeutic modalities for cancer patients infected with SARS-CoV-2 or other coronavirusesanticipated to cause future pandemics.