GABARAPL1 is important for the activation of HRI during eIF2α phosphorylation-dependent stress response to sodium arsenite.

Sodium arsenite is known to activate the integrated stress response pathway, through the activation of the heme-regulated inhibitor kinase (HRI). Upon activation, HRI phosphorylates the α subunit of the translation initiation factor eIF2, resulting in cap-dependent translation arrest. As a consequence, untranslated mRNAs will be condensed into non-membranous cytoplasmic structures called stress granules, which will protect them in favor of the stress response. GABARAPL1 belongs to the ATG8 protein family involved in and out of the stress response mechanism so called autophagy. In this study, we investigated the role of the GABARAPL1 protein during the sodium arsenite stress response in A549 cells. Interestingly, in the absence of GABARAPL1, we observed a decrease in eIF2α phosphorylation, as well as a defect in stress granules formation. We therefore propose a new model in which GABARAPL1 facilitates the interaction between HSP90 and HRI, which is required for full activation of this kinase during the p-eIF2α-dependent stress response upon exposure to sodium arsenite. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-44621-2.