Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs)

Abstract

Non-communicable diseases (NCDs) are medical conditions that, by definition, are non-infectious and non-transmissible among people. Much of current NCDs are generally due to genetic, behavioral, and metabolic risk factors that often include excessive alcohol consumption, smoking, obesity, and untreated elevated blood pressure, and share many common signal transduction pathways. Alterations in cell and physiological signaling and transcriptional control pathways have been well studied in several human NCDs, but these same pathways also regulate expression and function of the protein synthetic machinery and mRNA translation which have been less well investigated. Alterations in expression of specific translation factors, and disruption of canonical mRNA translational regulation, both contribute to the pathology of many NCDs. The two most common pathological alterations that contribute to NCDs discussed in this review will be the regulation of eukaryotic initiation factor 2 (eIF2) by the integrated stress response (ISR) and the mammalian target of rapamycin complex 1 (mTORC1) pathways. Both pathways integrally connect mRNA translation activity to external and internal physiological stimuli. Here, we review the role of ISR control of eIF2 activity and mTORC1 control of cap-mediated mRNA translation in some common NCDs, including Alzheimer’s disease, Parkinson’s disease, stroke, diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease (COPD), and cardiac diseases. Our goal is to provide insights that further the understanding as to the important role of translational regulation in the pathogenesis of these diseases.

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“…The top 1 ingenuity canonical pathway was EIF2 signaling, and this (Figure 7D), together with the IPA on ribosome protein genes, further confirmed that EIF2 signaling was the key driver of the TNBC metastasis in human. To further confirm that, we checked the expression of the major component genes of EIF2 signaling and found upregulation of multiple genes, including EIF2AK1 (HRI protein coding gene), EIF2AK2 (PKR protein coding gene), EIF2AK4 (GCN2 protein coding gene), EIF2B5, and AKT2 (Figure 7E; Rios-Fuller et al, 2020). Other ingenuity canonical pathways included regulation of eIF4 and p70S6K signaling and mTOR signaling (Figure 7D), both of which were closely associated with TNBC biological activities (Madden et al, 2014;Wang et al, 2017;Zagorac et al, 2018).…”