Molecular basis of SIFI activity in the integrated stress response.

ABSTRACT: Chronic stress response activation impairs cell survival and causes devastating degenerative diseases^1-3. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase silencing factor of the integrated stress response (SIFI), to terminate stress response signalling and ensure cellular homeostasis⁴. How a silencing factor can sense stress across cellular scales to elicit timely stress response inactivation is poorly understood. Here we combine cryo-electron microscopy analysis of endogenous SIFI with AlphaFold modelling and biochemical studies to report the structural and mechanistic basis of the silencing of the integrated stress response. SIFI detects both stress indicators and stress response components through flexible domains within an easily ac

SUBMITTER: Yang Z 

PROVIDER: S-EPMC12286842 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature