Proteolytic activation of fatty acid synthase signals pan-stress resolution

Chronic stress and inflammation are not only outcomes of pathological states but rather major drivers of many human diseases [1][1]-[4][2]. Ideally, a given stress program is downregulated to basal levels upon restoration of homeostasis. Chronic responsiveness despite stress mitigation suggests a failure to sense the resolution of the initiating stressor. Here we show that a proteolytic cleavage event of fatty acid synthase (FASN) activates a global cue for stress resolution. FASN is well-established as the multifunctional enzyme catalyzing de novo biosynthesis of saturated fatty acid [5][3], [6][4]. Surprisingly, our results demonstrate FASN functioning as a signaling molecule promoting an anti-inflammatory profile apart from fatty acid synthesis. Redox-dependent proteolytic cleavage of FASN by caspase activates a truncated C-terminal enzymatic fragment (FASN-CTF) that is sufficient to down-regulate multiple aspects of stress-responsiveness including gene expression and metabolic programs. Only a fraction of FASN is cleaved allowing for continued fat synthesis. FASN-CTF can signal stress resolution across tissues in a cell non-autonomous manner. Consistent with these findings, FASN processing is also seen in well-fed but not fasted mouse liver. As down-regulation of stress responsiveness is critical to health, our findings provide a potential pathway to control the magnitude for diverse aspects of stress responses. ### Competing Interest Statement RJD is a founder and advisor for Atavistik Bioscience, and an advisor for Agios Pharmaceuticals, Vida Ventures and Droia Ventures. [1]: #ref-1 [2]: #ref-4 [3]: #ref-5 [4]: #ref-6