The integrated stress response manifests with the phosphorylation of eukaryotic initiation factor 2α (eIF2α) on serine residue 51 and plays a major role in the adaptation of cells to endoplasmic reticulum stress in the initiation of autophagy and in the ignition of immune responses. Here, we report that lysosomotropic agents, including azithromycin, chloroquine, and hydroxychloroquine, can trigger eIF2α phosphorylation in vitro (in cultured human cells) and, as validated for hydroxychloroquine, in vivo (in mice). Cells bearing a non-phosphorylatable eIF2α mutant (S51A) failed to accumulate autophagic puncta in response to azithromycin, chloroquine, and hydroxychloroquine. Conversely, two inhibitors of eIF2α dephosphorylation, nelfinavir and salubrinal, enhanced the induction of such autophagic puncta. Altogether, these results point to the unexpected capacity of azithromycin, chloroquine, and hydroxychloroquine to elicit the integrated stress response.

整合的应激反应表现为真核起始因子 2α (eIF2α) 在丝氨酸残基 51 上的磷酸化，并在细胞适应内质网应激、启动自噬和引发免疫反应中发挥重要作用。在这里，我们报道了溶酶体药物，包括阿奇霉素、氯喹和羟氯喹，可以在体外（在培养的人类细胞中）触发 eIF2α 磷酸化，并且经羟氯喹验证，可以在体内（在小鼠中）触发 eIF2α 磷酸化。携带不可磷酸化 eIF2α 突变体 (S51A) 的细胞无法响应阿奇霉素、氯喹和羟氯喹积累自噬点。相反，两种 eIF2α 去磷酸化抑制剂奈非那韦和 salubrinal 增强了这种自噬斑点的诱导。总而言之，这些结果表明阿奇霉素、氯喹和羟氯喹具有意想不到的引发综合应激反应的能力。