Multiprotein bridging factor 1 is required for robust activation of the integrated stress response on collided ribosomes

Description

The multiprotein bridging factor 1 (Mbf1) proteins comprise a family of conserved eukaryotic proteins thought to mediate the activity of stress-induced transcription factors. In yeast, Mbf1 has been proposed to function in the integrated stress response (ISR) by mediating a direct interaction between the basal transcription machinery and the process’s key effector Gcn4. Curiously, mounting recent evidence has strongly suggested that the factor (and its human homologue) is recruited to collided ribosomes, the very signal newly recognized to activate the ISR. Here we provide data that connect these otherwise seemingly disparate functions of Mbf1. Our findings reveal that Mbf1 functions as a core factor in the ISR process, responding early to stress and mediating the activation of Gcn2. We further show that the factor serves no role as a transcriptional coactivator of Gcn4; instead, Mbf1 and its human homologue are required for optimal stress-induced eIF2 phosphorylation and downstream de-repression of GCN4/ATF4 translation. Detailed mutational and biochemical analysis, together with a cryo-EM structure of the factor bound to collided ribosomes, shows that Mbf1’s contribution to the ISR is mediated through its interaction with ribosomes. Collectively, our data establish that Mbf1 functions in signaling by acting as a direct sensor of stress-induced ribosome collisions.

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