Fatty-acid receptor CD36 functions as a hydrogen sulfide-targeted receptor with its Cys333-Cys272 disulfide bond serving as a specific molecular switch to accelerate gastric cancer metastasis

Abstract Background Hydrogen Sulfide (H 2 S), a third member of gasotransmitter family along with nitric oxide (NO) and carbon monoxide (CO), exerts a wide range of cellular and molecular actions in our body. There is a large body of evidence suggesting that H 2 S plays an important role in cancer metastasis; however, the molecular mechanisms of H 2 S-mediated acceleration of cancer metastasis remain unknown. Methods We examined the promote effects of H 2 S on phenotype of gastric cancer (GC) cells (including those of express wild type CD36 and mutant CD36) in vitro and in vivo . GC patients' samples were used for clinical translational significance evaluation. Findings H 2 S triggered lipid metabolism reprogramming by significantly up-regulating the expression of the fatty-acid receptor CD36 (CD36) and directly activating CD36 in GC cells. Mechanistically, a disulfide bond located between cysteine (Cys)333 and Cys272 within the CD36 protein structure that was labile to H 2 S-mediated modification. The long chain-fatty acid (LC-FA) binding pocket was capped by a turn in the CD36 protein, located between helical and sheet structures that were stabilized by the Cys333-Cys272. This limited the secondary binding between LC-FAs and lysine (Lys)334. Breaking the Cys333-Cys272 disulfide bond restored the second LC-FA binding conformation of CD36. Targeting CD36 in vivo blocked H 2 S-promoted metastasis and improved animal survival. Interpretation These findings identify that the Cys333-Cys272 disulfide bond disrupted the integrity of the second LC-FA binding conformation of CD36. Therefore, CD36 can directly activate LC-FA access to the cytoplasm by acting as a direct target molecule for H 2 S.