Chronic activation of the unfolded protein response (UPR), notably the branch comprising the kinase PERK and the translation initiation factor eIF2α, is a pathological feature of many neurodegenerative diseases caused by protein misfolding. Partial reduction of UPR signaling at the level of phosphorylated eIF2α is neuroprotective and avoids the pancreatic toxicity caused by full inhibition of PERK kinase activity. However, other stress pathways besides the UPR converge on phosphorylated eIF2α in the integrated stress response (ISR), which is critical to normal cellular function. We explored whether partial inhibition of PERK signaling may be a better therapeutic option. PERK-mediated phosphorylation of eIF2α requires its binding to the insert loop within PERK’s kinase domain, which is, itself, phosphorylated at multiple sites. We found that, as expected, Akt mediates the phosphorylation of Thr⁷⁹⁹ in PERK. This phosphorylation event reduced eIF2α binding to PERK and selectively attenuated downstream signaling independently of PERK activity and the broader ISR. Induction of Thr⁷⁹⁹ phosphorylation with a small-molecule activator of Akt similarly reduced PERK signaling and increased both neuronal and animal survival without measurable pancreatic toxicity in a mouse model of prion disease. Thus, promoting PERK phosphorylation at Thr⁷⁹⁹ to partially down-regulate PERK-eIF2α signaling while avoiding widespread ISR inhibition may be a safe therapeutic approach in neurodegenerative disease.

未折叠蛋白反应 (UPR) 的慢性激活，特别是包含激酶 PERK 和翻译起始因子 eIF2α 的分支，是许多由蛋白质错误折叠引起的神经退行性疾病的病理特征。在磷酸化 eIF2α 水平上部分降低 UPR 信号具有神经保护作用，并避免了完全抑制 PERK 激酶活性引起的胰腺毒性。然而，除 UPR 之外的其他应激途径集中在综合应激反应 (ISR) 中的磷酸化 eIF2α，这对正常细胞功能至关重要。我们探讨了部分抑制 PERK 信号是否可能是更好的治疗选择。PERK 介导的 eIF2α 磷酸化需要它与 PERK 激酶结构域内的插入环结合，该结构域本身在多个位点磷酸化。我们发现，PERK ⁷⁹⁹。这种磷酸化事件减少了 eIF2α 与 PERK 的结合，并独立于 PERK 活性和更广泛的 ISR 选择性地减弱了下游信号传导。在朊病毒病小鼠模型中，用 Akt 的小分子激活剂诱导 Thr ⁷⁹⁹磷酸化同样减少了 PERK 信号并增加了神经元和动物的存活率，而没有可测量的胰腺毒性。因此，在 Thr ⁷⁹⁹处促进 PERK 磷酸化以部分下调 PERK-eIF2α 信号传导，同时避免广泛的 ISR 抑制可能是神经退行性疾病的安全治疗方法。