A study identifies a ubiquitin-dependent mechanism involving the E3 ligase SIFI that silences the cellular response to mitochondrial protein import stress. SIFI, mutated in ataxia and early-onset dementia, degrades both unimported mitochondrial precursors and stress response components by recognizing shared sequence motifs that encode protein localization and stability. This process ensures timely termination of stress responses, preventing apoptosis and maintaining cellular health. The study shows that pharmacological silencing of stress responses can restore cell survival in SIFI mutant cells, highlighting the importance of signal termination in neurodegenerative diseases. SIFI targets proteins such as DELE1 and HRI, which are involved in the integrated stress response (ISR). The research reveals that SIFI recognizes converging degrons, which are motifs that encode both protein localization and stability. These degrons allow SIFI to distinguish between mitochondrial precursors and other proteins, ensuring accurate silencing of stress responses after specific stress events have been resolved. The findings suggest that SIFI plays a key role in regulating stress response silencing, which is crucial for maintaining cellular homeostasis and preventing neurodegenerative diseases. The study also demonstrates that pharmacological stress response silencing can rescue cells with mitochondrial import defects, offering a potential therapeutic approach for neurodegenerative diseases.A study identifies a ubiquitin-dependent mechanism involving the E3 ligase SIFI that silences the cellular response to mitochondrial protein import stress. SIFI, mutated in ataxia and early-onset dementia, degrades both unimported mitochondrial precursors and stress response components by recognizing shared sequence motifs that encode protein localization and stability. This process ensures timely termination of stress responses, preventing apoptosis and maintaining cellular health. The study shows that pharmacological silencing of stress responses can restore cell survival in SIFI mutant cells, highlighting the importance of signal termination in neurodegenerative diseases. SIFI targets proteins such as DELE1 and HRI, which are involved in the integrated stress response (ISR). The research reveals that SIFI recognizes converging degrons, which are motifs that encode both protein localization and stability. These degrons allow SIFI to distinguish between mitochondrial precursors and other proteins, ensuring accurate silencing of stress responses after specific stress events have been resolved. The findings suggest that SIFI plays a key role in regulating stress response silencing, which is crucial for maintaining cellular homeostasis and preventing neurodegenerative diseases. The study also demonstrates that pharmacological stress response silencing can rescue cells with mitochondrial import defects, offering a potential therapeutic approach for neurodegenerative diseases.