Dihydrocapsaicin induces translational repression and stress granule through HRI-eIF2α phosphorylation axis

• Published in: Biochemical and biophysical research communications 2022-01, Vol.588, p.125-132
• Main Authors: De, Koushitak, Jayabalan, Aravinth Kumar, Mariappan, Ramesh, Ramasamy, Vijay Sankar, Ohn, Takbum
• Format: Article
• Language: English
• Subjects: Animals; Biomolecular condensates; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Cell Line; Dihydrocapsaicin; eIF-2 Kinase - metabolism; Enzyme Activation - drug effects; Eukaryotic Initiation Factor-2 - metabolism; Humans; Mice; Oxidative Stress - drug effects; Phosphorylation - drug effects; Polyribosomes - drug effects; Polyribosomes - metabolism; Protein Biosynthesis - drug effects; Stress granule; Stress Granules - drug effects; Stress Granules - metabolism; Stress kinases; Translation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.12.049

Stress granules (SGs) are cytoplasmic biomolecular condensates that are formed against a variety of stress conditions when translation initiation is perturbed. SGs form through the weak protein-protein, protein-RNA, and RNA-RNA interactions, as well as through the intrinsically disordered domains and post-translation modifications within RNA binding proteins (RBPs). SGs are known to contribute to cell survivability by minimizing the stress-induced damage to the cells by delaying the activation of apoptosis. Here, we find that dihydrocapsaicin (DHC), an analogue of capsaicin, is a SG inducer that promotes polysome disassembly and reduces global protein translation via phosphorylation of eIF2α. DHC-mediated SG assembly is controlled by the phosphorylation of eIF2α at serine 51 position and is controlled by all four eIF2α stress kinases (i.e., HRI, PKR, PERK, and GCN2) with HRI showing maximal effect. We demonstrate that DHC is a bonafide compound that induces SG assembly, disassembles polysome, phosphorylates eIF2α in an HRI dependent manner, and thereby arrest global translation. Together, our results suggest that DHC is a novel SG inducer and an alternate to sodium arsenite to study SG dynamics. •Dihydrocapsaicin promotes stress granule assembly and processing body formation.•Dihydrocapsaicin treatment disassembles polysome and then reinitiate polysome assembly during prolonged stress.•Dihydrocapsaicin treatment selectively translates low molecular weight proteins.•Dihydrocapsaicin phosphorylates eIF2α through activation of HRI (EIF2AK1) kinase.