DELE1 oligomerization promotes integrated stress response activation.
DELE1 oligomerization promotes integrated stress response activation.
复制标题
DELE1 寡聚化促进整合应激反应激活。
DOI：
10.1038/s41594-023-01061-0
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发表时间：
2023
影响因子：
16.8
通讯作者：
Lander,GabrielC
中科院分区：
文献类型：
--
作者：
Yang,Jie;Baron,KelseyR;Pride,DanielE;Schneemann,Anette;Guo,Xiaoyan;Chen,Wenqian;Song,AlbertS;Aviles,Giovanni;Kampmann,Martin;Wiseman,RLuke;Lander,GabrielC
Mitochondria are dynamic organelles that continually respond to cellular stress. Recent studies have demonstrated that mitochondrial stress is relayed from mitochondria to the cytosol by the release of a proteolytic fragment of DELE1 that binds to the eIF2α kinase HRI to initiate integrated stress response (ISR) signaling. We report the cryo-electron microscopy structure of the C-terminal cleavage product of human DELE1, which assembles into a high-order oligomer. The oligomer consists of eight DELE1 monomers that assemble withD4symmetry via two sets of hydrophobic inter-subunit interactions. We identified the key residues involved in DELE1 oligomerization, and confirmed their role in stabilizing the octamer in vitro and in cells using mutagenesis. We further show that assembly-impaired DELE1 mutants are compromised in their ability to induce HRI-dependent ISR activation in cell culture models. Together, our findings provide molecular insights into the activity of DELE1 and how it signals to promote ISR activity following mitochondrial insult.
