mTORC1-Sch9 regulates hydrogen sulfide production through the transsulfuration pathway
mTORC1-Sch9 regulates hydrogen sulfide production through the transsulfuration pathway
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mTORC1-Sch9 通过转硫途径调节硫化氢的产生
DOI：
10.18632/aging.102327
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发表时间：
2019-10-15
期刊：
影响因子：
5.2
通讯作者：
Liu，Ke
中科院分区：
文献类型：
--
作者：
Lyu，Zhou;Gao，Xuejie;Liu，Ke
内源性硫化氢介导饮食限制（DR）的抗衰老作用。然而，目前尚不清楚H2S的产生是如何通过与DR相关的途径调节的。由于mTORC1途径在DR中的重要性，我们研究了Sch9（哺乳动物S6K1的酵母同源物和mTORC1的主要底物）对酵母中H2S产生的影响。我们发现，通过SCH9缺失、雷帕霉素或肉豆素处理抑制mTORC1-Sch9通路可导致H2S产生显著减少。虽然SCH9缺乏没有改变细胞内蛋氨酸水平，但在Δsch9细胞中，细胞内半胱氨酸水平升高。在mTORC1-Sch9抑制下，编码胱硫氨酸γ -裂解酶（CGL）和胱硫氨酸β -合成酶（CBS）的转硫途径基因CYS3和CYS4的表达也下降。在Δsch9细胞或经雷帕霉素处理的WT细胞中，过表达CYS3或CYS4可改善H2S产生的缺陷。最后，我们还观察到，在经过雷帕霉素处理的培养的人细胞中，H2S的产生减少，CGL和CBS的mRNA和蛋白水平降低，从而降低了mTORC1通路的活性。因此，我们的研究结果揭示了一个可能保守的机制，即通过转硫途径产生H2S是由mTORC1-Sch9信号通路调节的。
Endogenous hydrogen sulfide mediates anti-aging benefits of dietary restriction (DR). However, it is unclear how H2S production is regulated by pathways related to DR. Due to the importance of mTORC1 pathway in DR, we investigated the effects of Sch9, a yeast homolog of mammalian S6K1 and a major substrate of mTORC1 on H2S production in yeast Saccharomyces cerevisiae. We found that inhibition of the mTORC1-Sch9 pathway by SCH9 deletion, rapamycin or myriocin treatment resulted in a dramatic decrease in H2S production. Although deficiency of SCH9 did not alter the intracellular level of methionine, the intracellular level of cysteine increased in Δsch9 cells. The expression of CYS3 and CYS4, two transsulfuration pathway genes encoding cystathionine gamma-lyase (CGL) and cystathionine beta-synthase (CBS), were also decreased under mTORC1-Sch9 inhibition. Overexpression of CYS3 or CYS4 in Δsch9 cells or WT cells treated with rapamycin rescued the deficiency of H2S production. Finally, we also observed a reduction in H2S production and lowering of both mRNA and protein levels of CGL and CBS in cultured human cells treated with rapamycin to reduce mTORC1 pathway activity. Thus, our findings reveal a probably conserved mechanism in which H2S production by the transsulfuration pathway is regulated by mTORC1-Sch9 signaling.