Proteolytic Activation of Fatty Acid Synthase Controls Pan-Stress Response_Datasets

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.为限制过度应激反应引发的组织损伤，动物需精准评估应激事件，并感知应激源已得到缓解。然而，不同类型应激源的强度是否通过通用机制进行调控，目前尚不清楚。本研究发现，秀丽隐杆线虫（C. elegans）体内半胱天冬酶（caspase）对脂肪酸合酶（FASN-1）的蛋白水解切割，可激活应激缓解的全局信号，从而发挥解除警报信号的功能。由于半胱天冬酶介导的蛋白水解仅切割部分FASN-1，使其大部分结构保持完整，因此从头脂肪酸合成并未受到影响。FASN-1的切割会产生稳定的C端片段（FASN-CTF），该片段足以抑制ced-3半胱天冬酶突变体升高的应激响应水平。FASN-CTF可下调应激响应基因的表达、增强脂肪酸氧化并促进脂滴动态平衡。然而，在应激条件下人工过表达FASN-CTF会降低生物体存活率，这表明FASN-CTF并非缓解应激，而是一种强效信号，可抑制泛应激响应程序。作为半胱氨酸蛋白酶，半胱天冬酶的催化活性依赖于完全还原的半胱氨酸残基。本研究显示，在应激条件下，由于细胞环境氧化性增强，CED-3半胱天冬酶的蛋白水解激活活性在体内降低。因此，应激条件会通过抑制半胱天冬酶活性来阻止FASN-CTF的产生，从而使机体能够维持强烈的应激响应，表现为未折叠蛋白反应（Unfolded Protein Response, UPR）和先天免疫基因表达上调，同时伴随脂质封存。综上，我们的研究结果表明，半胱天冬酶切割FASN以产生FASN-CTF，可传递无应激状态的信号，并允许动用能量储备，进而限制机体对各类应激源的响应强度。