IRES-Dependent Translational Control during Virus-Induced Endoplasmic Reticulum Stress and Apoptosis

Abstract

Many virus infections and stresses can induce endoplasmic reticulum (ER) stress response, a host self-defense mechanism against viral invasion and stress. During this event, viral and cellular gene expression is actively regulated and often encounters a switching of the translation initiation from cap-dependent to internal ribosome-entry sites (IRES)-dependent. This switching is largely dependent on the mRNA structure of the 5′ untranslated region (5′ UTR) and on the particular stress stimuli. Picornaviruses and some other viruses contain IRESs within their 5′ UTR of viral genome and employ an IRES-driven mechanism for translation initiation. Recently, a growing number of cellular genes involved in growth control, cell cycle progression and apoptosis were also found to contain one or more IRES within their long highly structured 5′ UTRs. These genes initiate translation usually by a cap-dependent mechanism under normal physiological conditions; however, in certain environments, such as infection, starvation, and heat shock they shift translation initiation to an IRES-dependent modality. Although the molecular mechanism is not entirely understood, a number of studies have revealed that several cellular biochemical processes are responsible for the switching of translation initiation to IRES-dependent. These include the cleavage of translation initiation factors by viral and/or host proteases, phosphorylation (inactivation) of host factors for translation initiation, overproduction of homologous proteins of cap-binding protein eukaryotic initiation factors (eIF)4E, suppression of cap-binding protein eIF4E expression by specific microRNA, activation of enzymes for mRNA decapping, as well as others. Here, we summarize the recent advances in our understanding of the molecular mechanisms for the switching of translation initiation, particularly for the proteins involved in cell survival and apoptosis in the ER stress pathways during viral infections.

The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

“…Moreover, 4E-BP1, a negative regulator of cap-dependent mRNA translation, was found to be overexpressed in breast tumors compared to healthy epithelium, suggesting that translational mechanisms such as IRES might be active [50]. Interestingly, genes such as such as Apaf-1, DAP5, CHOP, p53, etc., that are also selectively translated by an IRES-driven mechanism, allow the cells to fine-tune their responses to cellular stress and, if conditions for cell survival are not restored, to proceed with final execution of apoptosis [51]. Although the significance of induction of ERα46 by cellular stress remains unknown, this isoform of ERα could be part of an orchestrated IRES-driven response, and contribute to slowing down of the proliferative response to E2.

Fig.

…”

Heat shock protein 70 promotes coxsackievirus B3 translation initiation and elongation via Akt-mTORC1 pathway depending on activation of p70S6K and Cdc2

“…To reveal the underlying mechanisms by which Hsp70 expression enhances CVB3 replication by modulating translation of the viral IRES‐containing RNA genome, we first focused on the translation initiation step, a major rate‐limiting phase tightly controlled by many factors, such as ITAFs (Hanson et al . , ; Komar & Hatzoglou, ). To this end, a HeLa cell line stably overexpressing the eGFP‐Hsp70 protein was established by plasmid transfection (see Figure a for the expression levels of different clones).…”

The DNA Virus White Spot Syndrome Virus Uses an Internal Ribosome Entry Site for Translation of the Highly Expressed Nonstructural Protein ICP35

“…Presently, we know very little about the mechanisms used by the few known examples of IRES-mediated translation that are found in a few DNA viruses. Nevertheless, for the DNA viruses, too, IRES-dependent translation is necessary for the efficient expression of some viral proteins and for survival of the virus under unfavorable conditions, such as the host-induced antiviral response or virus-induced host translation shutoff (13,35,61). IRES-mediated translation is also likely to be critically important for WSSV, especially since this virus produces so many polycistronic mRNAs (17,19,62).…”