We have identified the ES6S region of 40S ribosomal subunit as the gateway for mRNA entry and 43S-PIC scanning during translation initiation. Our data suggest the ES6S region could be serving as a platform for the recruitment of RNA helicases (eIF4A and DDX3, among others) involved in RNA secondary structure unwinding. Blocking ES6S region differentially affected translation of mRNAs encoding some proto-oncogenes (H-Ras, CCND3, ODC-1, etc.), genes involved in signal transduction with long and structured 5´UTR mRNAs and also some viral mRNAs. We are currently evaluating the ES6S region as a target for antitumoral and antiviral molecules.

More recently, we found that the differential effect of the non-structural protein 1 (NSP1) of SARS-CoV-2 on translation depends on the composition of 5’ UTR and codon usage bias of target mRNA. Our data suggest the existence of two mechanisms for the recruitment of mRNA to the 40S subunit (threading and slotting) and a functional interaction between the speed of elongation (codon bias) and translation initiation. We are also looking at the implications of our results for the molecular evolution of SARS-CoV-2 and other human respiratory viruses.

We continue to study the molecular and functional links among stress response, translational reprogramming and cellular homeostasis. Thus, we found that preventing eIF2α phosphorylation in yeast not only impaired stress response, but also accelerated aging by a mechanism that involves proteostasis and autophagy disruption. We have identified some genes involved in proteasome activity whose expression is regulated by eIF2α phosphorylation. We are characterizing the role of these genes in key processes regulating proteostasis such as protein aggregation, autophagy, mitophagy and how they can affect cell longevity.