Proteolytic Activation of Fatty Acid Synthase Controls Pan-Stress Response_Datasets

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In order to limit tissue damage caused by excessive stress responses, animals must accurately gauge stressful events as well as sense when a stressor has been mitigated. However, whether the magnitude of diverse stressors is measured by a general mechanism is unknown. In this study, we show that proteolytic cleavage of fatty acid synthase (FASN-1) in C. elegans by caspase activates a global cue of stress resolution, thus functioning as an all clear signal. As caspase-catalyzed proteolysis leaves the majority of FASN-1 intact, de novo fatty acid synthesis is unaffected. FASN-1 cleavage generates a stable C-terminal fragment (FASN-CTF) that is sufficient to suppress the elevated stress responsiveness of ced-3 caspase mutants. FASN-CTF down-regulates expression of stress-response genes, enhances fatty acid oxidation and promotes lipid droplet dynamics. However, artificially expressing FASN-CTF under stressful conditions compromises survival suggesting rather than mitigating stress, FASN-CTF is a potent signal to reduce pan-stress response programs. As cysteine proteases, catalytic activities of caspases are dependent on fully reduced cysteine. Under stressful conditions, we show that CED-3 caspase proteolytic activation decreases in vivo due to a more oxidative cellular environment. Consequently, stressful conditions prevent FASN-CTF generation by inhibiting caspase activity, thereby allowing robust stress response with enhanced expression of UPR and innate immunity genes along with sequestration of lipids. In summary, our findings suggest that caspase cleavage of FASN to generate FASN-CTF signals a stress-free state and licenses use of energy stores thereby limiting the magnitude of responsiveness to diverse stressors.

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