SARS-CoV-2 Nsp1 cooperates with initiation factors EIF1 and 1A to selectively enhance translation of viral RNA.

A better mechanistic understanding of virus-host dependencies can help reveal vulnerabilities and identify opportunities for therapeutic intervention. Of particular interest are essential interactions that enable production of viral proteins, as those could target an early step in the virus lifecycle. Here, we use subcellular proteomics, ribosome profiling analyses and reporter assays to detect changes in protein synthesis dynamics during SARS-CoV-2 (CoV2) infection. We identify specific translation factors and molecular chaperones that are used by CoV2 to promote the synthesis and maturation of its own proteins. These can be targeted to inhibit infection, without major toxicity to the host. We also find that CoV2 non-structural protein 1 (Nsp1) cooperates with initiation factors EIF1 and 1A to selectively enhance translation of viral RNA. When EIF1/1A are depleted, more ribosomes initiate translation from a conserved upstream CUG start codon found in all genomic and subgenomic viral RNAs. This results in higher translation of an upstream open reading frame (uORF1) and lower translation of the main ORF, altering the stoichiometry of viral proteins and attenuating infection. Replacing the upstream CUG with AUG strongly inhibits translation of the main ORF independently of Nsp1, EIF1, or EIF1A. Taken together, our work describes multiple dependencies of CoV2 on host biosynthetic networks and proposes a model for dosage control of viral proteins through Nsp1-mediated control of translation start site selection.

Organosulfur Compounds in Colorectal Cancer Prevention and Progression.

This work represents an overview of the current investigations involving organosulfur compounds and colorectal cancer. The molecules discussed in this review have been investigated regarding their impact on colorectal cancer directly, at the in vitro, in vivo, and clinical stages. Organosulfur compounds may have indirect effects on colorectal cancer, such as due to their modulating effects on the intestinal microbiota or their positive effects on intestinal mucosal health. Here, we focus on their direct effects via the repression of multidrug resistance proteins, triggering of apoptosis (via the inhibition of histone deacetylases, increases in reactive oxygen species, p53 activation, ß-catenin inhibition, damage in the mitochondrial membrane, etc.), activation of TGF-ß, binding to tubulin, inhibition of angiogenesis and metastasis mechanisms, and inhibition of cancer stem cells, among others. In general, the interesting positive effects of these nutraceuticals in in vitro tests must be further analyzed with more in vivo models before conducting clinical trials.