Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Radiation Oncology, the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Autophagy. 2022 Feb;18(2):309-319. doi: 10.1080/15548627.2021.1924038. Epub 2021 May 16.
S-adenosyl-l-homocysteine (SAH), an amino acid derivative, is a key intermediate metabolite in methionine metabolism, which is normally considered as a harmful by-product and hydrolyzed quickly once formed. AHCY (adenosylhomocysteinase) converts SAH into homocysteine and adenosine. There are two other members in the AHCY family, AHCYL1 (adenosylhomocysteinase like 1) and AHCYL2 (adenosylhomocysteinase like 2). Here we define AHCYL1 function as a SAH sensor to inhibit macroautophagy/autophagy through PIK3C3. The C terminus of AHCYL1 interacts with SAH specifically and the interaction with SAH promotes the binding of the N terminus to the catalytic domain of PIK3C3, resulting in inhibition of PIK3C3. More importantly, this observation was further validated , indicating that SAH functions as a signaling molecule. Our study uncovers a new axis of SAH-AHCYL1-PIK3C3, which senses the intracellular level of SAH to inhibit autophagy in an MTORC1-independent manner. ADOX: adenosine dialdehyde; AHCY: adenosylhomocysteinase; AHCYL1: adenosylhomocysteinase like 1; cLEU: cycloleucine; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3P: phosphatidylinositol-3-phosphate; SAH: S-adenosyl-l-homocysteine; SAM: S-adenosyl-l-methionine.
S-腺苷-L-同型半胱氨酸（SAH），一种氨基酸衍生物，是蛋氨酸代谢中的关键中间代谢产物，通常被认为是一种有害的副产物，一旦形成就会迅速水解。AHCY（腺苷同型半胱氨酸酶）将 SAH 转化为同型半胱氨酸和腺苷。AHCY 家族还有另外两个成员，AHCYL1（腺苷同型半胱氨酸酶样 1）和 AHCYL2（腺苷同型半胱氨酸酶样 2）。在这里，我们将 AHCYL1 的功能定义为 SAH 传感器，通过 PIK3C3 抑制巨自噬/自噬。AHCYL1 的 C 端与 SAH 特异性相互作用，与 SAH 的相互作用促进 N 端与 PIK3C3 的催化结构域结合，从而抑制 PIK3C3。更重要的是，这一观察结果得到了进一步验证，表明 SAH 是一种信号分子。我们的研究揭示了一个新的 SAH-AHCYL1-PIK3C3 轴，它感知细胞内 SAH 的水平，以一种不依赖于 MTORC1 的方式抑制自噬。ADOX：腺苷二醛；AHCY：腺苷同型半胱氨酸酶；AHCYL1：腺苷同型半胱氨酸酶样 1；cLEU：环亮氨酸；PIK3C3：磷脂酰肌醇 3-激酶催化亚单位 3；PtdIns3P：磷脂酰肌醇-3-磷酸；SAH：S-腺苷-L-同型半胱氨酸；SAM：S-腺苷-L-蛋氨酸。
