Cells respond to adverse environmental changes by activating stress response pathways. However, the continuous activation of stress responses can lead to unwanted cell death or damage to necessary biological functions, and it is not clear how stress response pathways are turned off once the condition improves. Haakonsen et al. have now reported the discovery of an E3 complex that switches off the stress response.

The team initiated their study by identifying genes that display synthetic lethality with UBR4, which encodes an E3 ligase that is mutated in early-onset dementia, through a genome-wide CRISPR–Cas9 screen. They found that most genetic interactors of UBR4 were associated with mitochondrial import. Affinity purification experiments revealed that UBR4 forms a complex with another E3 ligase, KCMF1, and calmodulin. Deletion of KCMF1 or calmodulin, or disruption of their interaction with UBR4, made cells more susceptible to mitochondrial import stress. This suggests that these three proteins function as a complex to ensure cell survival under mitochondrial stress.

细胞通过激活应激反应途径来应对不利的环境变化。然而，应激反应的持续激活可能会导致不必要的细胞死亡或必要的生物功能受损，而且目前尚不清楚一旦病情改善，应激反应途径如何关闭。哈康森等人。现在报告发现了一种可以关闭应激反应的 E3 复合物。

该团队通过全基因组 CRISPR-Cas9 筛选，鉴定了具有UBR4合成致死性的基因，该基因编码一种在早发性痴呆症中突变的 E3 连接酶，从而开始了他们的研究。他们发现UBR4的大多数遗传相互作用因子与线粒体输入有关。亲和纯化实验表明，UBR4 与另一种 E3 连接酶、KCMF1 和钙调蛋白形成复合物。 KCMF1 或钙调蛋白的缺失，或它们与 UBR4 相互作用的破坏，使细胞更容易受到线粒体输入应激的影响。这表明这三种蛋白质作为复合物发挥作用，以确保细胞在线粒体应激下生存。