生物通路：羊毛甾醇生物合成
中文名称
通路描述
胆固醇生物合成始于胞质乙酰 CoA 转化为羊毛甾醇的 15 步反应序列（Mitsche et al. 2015）。其中第三步，由β-羟甲基辅酶 A（bHMG-CoA）还原酶（HMGCR）催化将 bHMG-CoA 还原为甲戊二酸（MVA），是胆固醇生物合成中受严格调控、限速的关键步骤。该酶也是他汀类药物（statins）的作用靶点。在缺乏线粒体组装功能的突变小鼠中，胆固醇生物合成发生改变，表明羊毛甾醇合成的一些步骤可能在线粒体中进行（Faust & Kovacs 2014）。然而，这些效应可能是间接的，通过线粒体缺陷引起的细胞内 ER 应激反应介导，这与观察一致：即使缺乏功能性线粒体，突变小鼠或线粒体缺陷人类中涉及的胆固醇生物合成酶的功能也不受影响。因此，该通路的所有步骤均定位于胞质，由胞质或内质网膜相关酶催化。他汀类药物是一类降低血液中胆固醇水平的药物，其作用机制是通过抑制肝脏中参与胆固醇合成的酶——β-羟甲基辅酶 A（HMG-CoA）还原酶。
英文描述
GSK3B-mediated proteasomal degradation of PD-L1(CD274) Post-translational modifications (PTMs) of PD-L1 (CD274) play an important regulatory role in modulating immune tolerance in normal physiology. The same mechanism is hijacked by cancer cells to enable immune evasion (Hsu et al., 2018, Dai et al., 2022, Yu et al., 2021). PD-L1 protein levels are tightly controlled by multiple mechanisms such as phosphorylation, glycosylation, ubiquitination, etc. (Feng et al., 2023). GSK3B is a serine-threonine kinase known to be regulated by multiple growth factor signalling pathways like EGFR, WNT, etc. GSK3B is constitutively active and phosphorylation by upstream pathways inactivates its kinase activity. GSK3B regulates PD-L1 protein stability and glycosylation. GSK3B phosphorylation of PD-L1 at T180 and S184 induces proteasomal degradation of PD-L1 and inhibits its glycosylation. GSK3B-induced phosphorylation facilitates binding of PD-L1 with β-TrCP (BTRC), a substrate recognition subunit of the SCF E3 ubiquitin ligase complex, which promotes PD-L1 ubiquitination and routes it for proteasomal degradation (Li et al, 2016, Schulz et al., 2019). Moreover, MET phosphorylates GSK3B at tyrosine 56, resulting in GSK3B activation and promotion of PD-L1 degradation (Li etal, 2019).
所含基因
44 个基因