14. During eukaryotic protein synthesis, stress conditions result in activation of specific kinases leading to phosphorylation of a key translation initiation factor that inhibits protein synthesis from a large number of cellular mRNA. Which one of the following factors is the target of the kinase?
(1) elF4E      (2) elF4G
(3) elF2a      (4) Gcn4

Introduction

Cells exposed to various stress conditions rapidly reduce global protein synthesis to conserve resources and prevent accumulation of misfolded proteins. A key molecular event mediating this response is the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α). This modification acts as a molecular switch that inhibits translation initiation, allowing cells to adapt and survive under adverse conditions.

The Role of eIF2α in Translation Initiation

eIF2 is a heterotrimeric protein complex essential for the initiation of translation. Its alpha subunit (eIF2α) binds GTP and initiator methionyl-tRNA to form a ternary complex, which delivers the initiator tRNA to the ribosome. After start codon recognition, eIF2 hydrolyzes GTP to GDP and must be recycled back to the GTP-bound form by the guanine nucleotide exchange factor eIF2B to participate in another round of initiation.

Phosphorylation of eIF2α and Its Consequences

Stress-activated kinases phosphorylate eIF2α on serine 51, increasing its affinity for eIF2B and effectively sequestering eIF2B. This sequestration prevents GDP-GTP exchange, reducing ternary complex formation and stalling translation initiation.

This mechanism leads to:

• Global reduction in protein synthesis, conserving energy and reducing the load on the protein folding machinery.

• Selective translation of specific mRNAs, such as ATF4, which contain upstream open reading frames (uORFs) that enable their translation under these conditions.

Stress-Activated eIF2α Kinases

Four well-characterized kinases phosphorylate eIF2α in response to distinct stress signals:

• PERK: Activated by endoplasmic reticulum stress.

• GCN2: Activated by amino acid starvation.

• PKR: Activated by viral infection and double-stranded RNA.

• HRI: Activated by heme deficiency and oxidative stress.

This phosphorylation event is central to the integrated stress response (ISR), coordinating cellular adaptation to diverse stresses.

Conclusion

Phosphorylation of eIF2α is the key regulatory event that inhibits global protein synthesis during stress. By targeting eIF2α, cells efficiently downregulate translation initiation, conserve resources, and selectively translate stress-responsive genes, ensuring survival under adverse conditions.

Answer:
(3) eIF2α