上海交通大学吴方等研究人员合作发现，胱硫醚γ-裂解酶衍生的H₂S通过对鞘磷脂-1-磷酸裂解酶的异构抑制作用负向调节胸腺迁出。相关论文于2024年6月24日在线发表于国际学术期刊《中国药理学报》。

研究人员表示，胸腺迁出是胸腺细胞成熟的关键过程，由鞘磷脂-1-磷酸裂解酶（S1PL）严格调控。最近，胱硫醚γ-裂解酶（CSE）作为产生硫化氢（H₂S）的酶之一，已成为一种重要的免疫过程调节剂。然而，CSE、H₂S 和胸腺迁出之间的分子联系在很大程度上仍未得到探索。

研究人员揭示了CSE在免疫细胞胸腺迁出过程中的调控功能。研究人员发现，基因敲除CSE或使用CSE酶抑制剂NSC4056或D,L-丙炔甘氨酸（PAG）进行药物抑制，可显著增强成熟淋巴细胞和单核细胞从胸腺向外周血的迁移，而这种重新分布效应可通过外源H₂S供体NaHS的处理逆转。此外，CSE产生的H₂S还能显著提高小鼠外周血、胸腺和脾脏中的S1P水平，抑制促炎细胞因子的产生，并在细胞和体内挽救病原体诱导的败血症。值得注意的是，H₂S或多硫化物抑制了S1PL在细胞和体外纯化酶测定中的活性。

研究人员发现这种抑制作用依赖于新发现的邻近酶活性位点的C²⁰³XC²⁰⁵氧化还原基团，从而揭示了S1PL调节的生化机制。总之，这项研究发现了CSE衍生的H₂S在胸腺迁出中的新功能和机制，并为治疗S1P相关免疫疾病提供了潜在的药物靶点。

附：英文原文

Title: Cystathionine γ-lyase-derived H2S negatively regulates thymic egress via allosteric inhibition of sphingosine-1-phosphate lyase

Author: Hu, You-tian, Liu, Zhi-wei, Zhang, Tong-hui, Ma, Yu-e, He, Lei, Zhang, Jie, Zhou, Yue-yang, Vidal-Puig, Antonio, Pan, De-jing, Wu, Fang

Issue&Volume: 2024-06-24

Abstract: Thymic egress is a crucial process for thymocyte maturation, strictly regulated by sphingosine-1-phosphate lyase (S1PL). Recently, cystathionine γ-lyase (CSE), one of the enzymes producing hydrogen sulfide (H2S), has emerged as a vital immune process regulator. However, the molecular connection between CSE, H2S and thymic egress remains largely unexplored. In this study, we investigated the regulatory function of CSE in the thymic egress of immune cells. We showed that genetic knockout of CSE or pharmacological inhibition by CSE enzyme inhibitor NSC4056 or D,L-propargylglycine (PAG) significantly enhanced the migration of mature lymphocytes and monocytes from the thymus to the peripheral blood, and this redistribution effect could be reversed by treatment with NaHS, an exogenous donor of H2S. In addition, the CSE-generated H2S significantly increased the levels of S1P in the peripheral blood, thymus and spleen of mice, suppressed the production of proinflammatory cytokines and rescued pathogen-induced sepsis in cells and in vivo. Notably, H2S or polysulfide inhibited S1PL activity in cells and an in vitro purified enzyme assay. We found that this inhibition relied on a newly identified C203XC205 redox motif adjacent to the enzyme’s active site, shedding light on the biochemical mechanism of S1PL regulation. In conclusion, this study uncovers a new function and mechanism for CSE-derived H2S in thymic egress and provides a potential drug target for treating S1P-related immune diseases.

DOI: 10.1038/s41401-024-01322-8

Source: https://www.nature.com/articles/s41401-024-01322-8