Figure 2.

Translation arrest is a ‘subroutine’ of certain classes of endogenous cellular stress responses. Exogenous stressors induce damage to intracellular protein systems. Cellular damage-detection mechanisms activate in response to accumulation of damaged cell components. Damage detection mechanisms either couple to or are effectors that, in parallel, lead to transient inhibition of protein synthesis and induce transcription of mRNAs coding for stress proteins. Stress-induced mRNAs escape translation arrest, and are translated by ‘nonclassical’ initiation mechanisms such as by-pass scanning or internal ribosome entry site initiation. Translation arrest is initiated, usually by eIF2α phosphorylation, maintained in stress granules, and terminated after successful execution of the stress response program. Success in execution of the stress response program leads to repair of cell damage and recovery of general protein synthesis. If cell damage overwhelms the capacity of the cell's stress response, cell death mechanisms are triggered, and general protein synthesis never fully recovers. Ischemia and reperfusion-induced translation arrest is thus a specific example of this more general cellular response.