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

Onur Deniz, Ying Liu, Tuuli Kirkinen, Krista Kokki, Kateryna Gaertner, Pau Clavell-Revelles, Jaakko Mattila, Ville Hietakangas

Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland. · pubmed

Paper

Abstract

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 a 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 Drosophila melanogaster. Salr activates catabolic gene expression and restricts mTORC1-mediated cell growth in the Drosophila fat body. The genomic binding of Salr overlaps extensively with that of FoxO, and a similar convergence is observed for 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. Taken together, we show that Salr and FoxO are growth-inhibitory transcription factors that act in a convergent manner to respond to nutrient stress through distinct cues.

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Research summary

The study identifies Spalt-related (Salr) as a novel negative regulator of mTORC1-mediated growth that acts in parallel to FoxO to restrict cell growth and lipid storage during nutrient stress. This work is relevant because it elucidates a specific molecular mechanism linking the integrated stress response to the inhibition of anabolic growth pathways, which are central drivers of aging, although the findings represent an incremental identification of a regulatory node rather than a transformative breakthrough.

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