You are part of a group of first responders traveling to Japan where a new virus

Question

You are part of a group of first responders traveling to Japan where a new virus has emerged. Your task is to characterize how the virus takes control over human cells. At first, you suspect that translation will be affected. You take the lead on developing a set of experiments that will help understanding the underlying mechanisms of translation upon virus infection. Your team has been able to isolate viral mRNA from infected patient.

After analyzing the sequence for potential ORF, you realize that a complex structure might be forming in the 5’UTR.

What could be the structure and how could the structure influence the type of translation initiation mechanism being used? Describe both types.

Explanation / Answer

The complex structure might be a hair-pin loop which is formed in the 5' UTR. Similar to other positive-strand RNA viruses, the non-coding regions the 5' and 3' untranslated regions (5'UTR and 3'UTR), contain important sequence and structural elements critical for translation and RNA replication.

The 5'UTR harbors an internal ribosome entry site (IRES) that directs viral protein translation via a cap-independent mechanism. As the initiation sites for RNA synthesis, both 5'UTR and 3'UTR contain signals that are indispensable for and regulate viral RNA replication. Additional structural elements involved in translation or RNA replication are also present in both ends of the protein coding regions. These RNA elements interact with each other either directly or through the binding of viral and cellular proteins that are most likely involved in the regulation of translation and RNA replication processes. Since RNA replication and translation occur on the same RNA molecule, mechanisms must exist to regulate and separate these two processes.

Viruses face enormous pressures to maintain a “functional” genome size, which greatly influences the rate and efficiency of viral replication. Thus, host translational dependence may in part reflect the limitations placed on viral replication due to the enormous genome capacity that would be needed to encode the components for autonomous viral protein synthesis. This idea is supported by the highly specialized nature of the protein synthetic machinery, which encompasses well over 30 different gene products and yet remains highly conserved between the prokaryotic and eukaryotic kingdoms. Eukaryotic viruses have evolved effective means of exploiting their innate translational dependence through mechanisms of translational programming.

This is the process in which eukaryotic viruses (i) redirect the host translation machinery to favor viral protein synthesis and (ii) control the expression of their own gene products. The latter is especially important for the RNA viruses, which have limited transcriptional control and rely heavily on translational control strategies to modulate viral gene expression. Translational programming, such as the use of regulatory upstream open reading frame(s) (uORFs), overlapping reading frames, multicistronic transcripts, and termination control, allows viruses to conserve the functional genome size by making efficient use of genome coding capacity. In general, the mechanisms of translational programming are intrinsic to the structure of the viral mRNA itself. Structural elements within a viral mRNA that affect translational efficiency or impart translational control include the length and structural complexity of the untranslated regions (UTR), the position and context of the initiator AUG codon, the stability and accessibility of the of the m7G cap and the cap-binding complex, and the presence of uORF(s) preceding the major cistron. In addition, cis-acting sequence elements that recruit or bind trans-acting factors can impart an additional level of translational control to viral mRNA by facilitating translational selectivity.

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