Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway
Autor: | Ke Xu, Ruilin Tian, Arun P. Wiita, M. Almira Correia, Giovanni Aviles, Xiaoyan Guo, Yu-Hsiu T. Lin, Martin Kampmann, Yi Liu, Bret A. Unger |
---|---|
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Male General Science & Technology Physiological Eukaryotic Initiation Factor-2 Mitochondrion Stress Article Cell Line Mitochondrial Proteins 03 medical and health sciences eIF-2 Kinase 0302 clinical medicine Cytosol Genetics Integrated stress response Initiation factor Humans Phosphorylation Inner mitochondrial membrane CRISPR interference Multidisciplinary Chemistry ATF4 Metalloendopeptidases Activating Transcription Factor 4 Cell biology Mitochondria Enzyme Activation 030104 developmental biology Generic health relevance CRISPR-Cas Systems 030217 neurology & neurosurgery Molecular Chaperones Protein Binding |
Zdroj: | Nature, vol 579, iss 7799 Nature |
Popis: | In mammalian cells, mitochondrial dysfunction triggers the integrated stress response, in which the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) results in the induction of the transcription factor ATF41–3. However, how mitochondrial stress is relayed to ATF4 is unknown. Here we show that HRI is the eIF2α kinase that is necessary and sufficient for this relay. In a genome-wide CRISPR interference screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease; and DELE1, a little-characterized protein that we found was associated with the inner mitochondrial membrane. Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2α kinase activity of HRI. In addition, DELE1 is required for ATF4 translation downstream of eIF2α phosphorylation. Blockade of the OMA1–DELE1–HRI pathway triggers an alternative response in which specific molecular chaperones are induced. The OMA1–DELE1–HRI pathway therefore represents a potential therapeutic target that could enable fine-tuning of the integrated stress response for beneficial outcomes in diseases that involve mitochondrial dysfunction. A genome-wide CRISPR interference screen shows that a signalling pathway involving OMA1, DELE1 and the eIF2α kinase HRI relays mitochondrial stress to the cytosol to trigger the integrated stress response. |
Databáze: | OpenAIRE |
Externí odkaz: |