Spalt-related is an integrated stress response-activated inhibitor of mTORC1-mediated growth

Anabolic and catabolic processes are coordinated by a conserved regulatory network, which includes the nutrient sensing protein kinase mTOR complex 1 (mTORC1) and the insulin- and stress-responsive transcription factor FoxO. In physiological setting these regulators align growth, storage, reproduction, and aging with nutrient availability. Here, we identify transcription factor Spalt-related (Salr), previously implicated in organogenesis, as a negative regulator of growth and lipid storage. In the Drosophila fat body Salr activates catabolic gene expression and restricts mTORC1-mediated cell growth. The genomic binding of Salr overlaps extensively with that of FoxO and similar convergence is observed between their mammalian homologs SALL1 and FOXO1. Both Salr and FoxO are activated upon fasting but respond to distinct cues: while FoxO displays transient activation and is responsive to AKT inhibition, Salr is activated in a slow and sustained manner through the integrated stress response. Once activated, Salr counters nuclear localization of FoxO. Together, Salr and FoxO are converging transcriptional activators of catabolism during nutrient stress.