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.