Eukaryotic translation initiation factor 2 α phosphorylation as a therapeutic target in diabetes

Abstract

Regulation of mRNA translation is of vital importance for a cell to adapt to environmental changes. To serve this purpose, intricate mechanisms controlling mRNA translation have evolved, of which the eukaryotic initiation factors eIF2 and eIF4 represent essential regulatory nodes for both stress sensing and signal transduction. Stress sensing by eIF2 α subunit (eIF2α) kinases, translation regulation by eIF2α subunit phosphorylation and subsequent dephosphorylation constitute a core molecular switch for stress adaptation and rapid metabolic regulation. It is not surprising; therefore, that dysfunction of such a pathway is implicated in human disease, especially metabolic syndrome and diabetes. In theory, therapeutic intervention to target the eIF2α phosphorylation pathway provides a promising therapeutic solution to tackle this debilitating syndrome. Careful evaluation of such therapies is crucially needed considering the central role of eIF2α pathway in cellular function for every organ.

Keywords::

• diabetes
• endoplasmic reticulum
• eukaryotic translation initiation factor 2
• protein phosphorylation
• protein synthesis
• therapeutic approaches
• β cell failure

Financial & competing interests disclosure

RJ Kaufman is supported by NIH Grants: DK042394, DK088227, HL052173, and by Crohn’s and Colitis Foundation of America grant CCFA3800. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The endoplasmic reticulum (ER) is responsible for synthesis, modification and secretion of proteins, and alterations in this delicate system cause activation of the unfolded protein response (UPR).

• UPR activation is involved in many disorders and the importance of ER stress is linked to the pathogenesis of numerous human diseases, including diabetes.

• Reversible phosphorylation on the α subunit of eIF2 translation initiation factor serves as an essential molecular switch for protein synthesis regulation.

• Stress sensing by eukaryotic translation initiation factor 2 α (eIF2a) kinases and translational regulation by eIF2α Ser51 phosphorylation are vital for stress adaptation and cell survival under challenging environments, especially when the ER protein folding homeostasis is perturbed.

• Dysfunctional PERK-eIF2α-P signaling is associated with metabolic syndrome, including type I and type II diabetes.

• Type 2 diabetes mellitus is displayed when the functional β cell mass is compromised to a level where it no longer can maintain euglycemia.

• The requirement for a tightly regulated PERK-eIF2α pathway is established for normal β cell function and survival using several murine models, including the Ser51Ala eIF2α knock-in mutant mouse model.

• The potential for small molecular activators and inhibitors targeting the PERK-eIF2α pathway as therapeutics for diabetes is still under debate.

Notes