Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response

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...

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Bibliographic Details
Published in:Cell death & disease 2021-01, Vol.12 (1), p.6-6, Article 6
Main Authors: Tian, Ai-Ling, Wu, Qi, Liu, Peng, Zhao, Liwei, Martins, Isabelle, Kepp, Oliver, Leduc, Marion, Kroemer, Guido
Format: Article
Language:English
Subjects:
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96/35
96/47
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Animals
Anti-Bacterial Agents - pharmacology
Anti-Bacterial Agents - therapeutic use
Antibiotics
Antibodies
Autophagy
Azithromycin
Azithromycin - pharmacology
Azithromycin - therapeutic use
Biochemistry
Biomedical and Life Sciences
Cancer
Cell Biology
Cell Culture
Chloroquine
Chloroquine - pharmacology
Chloroquine - therapeutic use
Dephosphorylation
Endoplasmic reticulum
Humans
Hydroxychloroquine
Hydroxychloroquine - pharmacology
Hydroxychloroquine - therapeutic use
Immune response
Immunology
Initiation factor eIF-2α
Life Sciences
Medicin och hälsovetenskap
Mice
Nelfinavir
Phagocytosis
Phosphorylation
Serine
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-020-03324-w