BAG2 releases SAMD4B upon sensing of arginine deficiency to promote tumor cell survival

Abstract

Cells possess numerous metabolite sensors that detect essential nutrients for growth, with many directly binding to metabolites and responding to their levels. Given the vital role of arginine in various physiological and pathological processes, we hypothesized that there may be undiscovered sensors that detect arginine deficiency. Through a series of unbiased screening strategies in human cancer cell line models, we identified Bcl2-associated athanogene (BAG) family molecular chaperone regulator 2 (BAG2) as an arginine sensor, which could directly bind to arginine at the glutamine residue 167 (Q167). Upon arginine deficiency, BAG2 releases sterile alpha motif domain-containing protein 4B (SAMD4B), leading to β-catenin degradation to stabilize ATF4 protein, enhancing cell survival. When arginine is abundant, a strengthened binding between BAG2 and SAMD4B prevents β-catenin degradation, activating the Wnt/β-catenin pathway to support cell growth. Overall, our findings uncover an arginine-sensing pathway consisting of BAG2 and SAMD4B that promotes cancer cell adaptation to nutritional stress.

Keywords: BAG2; SAMD4B; arginine; cancer; metabolism; metabolite sensing; metabolite sensor.