Glycolipid transfer proteins (GLTPs) were first identified over three decades ago as ~24kDa, soluble, amphitropic proteins that specifically accelerate the intermembrane transfer of glycolipids. Upon discovery that GLTPs use a unique, all-α-helical, two-layer ‘sandwich’ architecture (GLTP-fold) to bind glycosphingolipids (GSLs), a new protein superfamily was born. Structure/function studies have provided exquisite insights defining features responsible for lipid headgroup selectivity and hydrophobic ‘pocket’ adaptability for accommodating hydrocarbon chains of differing length and unsaturation. In humans, evolutionarily-modified GLTP-folds have been identified with altered sphingolipid specificity, e. g. ceramide-1-phosphate transfer protein (CPTP), phosphatidylinositol 4-phosphate adaptor protein-2 (FAPP2) which harbors a GLTP-domain and GLTPD2. Despite the wealth of structural data (>40 Protein Data Bank deposits), insights into the in vivo functional roles of GLTP superfamily members have emerged slowly. In this review, recent advances are presented and discussed implicating human GLTP superfamily members as important regulators of: i) pro-inflammatory eicosanoid production associated with Group-IV cytoplasmic phospholipase A₂; ii) autophagy and inflammasome assembly that drive surveillance cell release of interleukin-1β and interleukin-18 inflammatory cytokines; iii) cell cycle arrest and necroptosis induction in certain colon cancer cell lines. The effects exerted by GLTP superfamily members appear linked to their ability to regulate sphingolipid homeostasis by acting in either transporter and/or sensor capacities. These timely findings are opening new avenues for future cross-disciplinary, translational medical research involving GLTP-fold proteins in human health and disease. Such avenues include targeted regulation of specific GLTP superfamily members to alter sphingolipid levels as a therapeutic means for combating viral infection, neurodegenerative conditions and circumventing chemo-resistance during cancer treatment.

糖脂转运蛋白 (GLTPs) 在 30 多年前首次被鉴定为约 24kDa 的可溶性两性蛋白，可特异性加速糖脂的膜间转移。在发现 GLTPs 使用独特的全α-螺旋、两层“三明治”结构 (GLTP-fold) 来结合糖鞘脂 (GSLs) 后，一个新的蛋白质超家族诞生了。结构/功能研究提供了精细的见解，定义了负责脂质头基选择性和疏水“口袋”适应不同长度和不饱和度的烃链的特征。在人类中，已经鉴定出具有改变的鞘脂特异性的进化修饰的 GLTP 折叠，例如神经酰胺 1-磷酸转移蛋白 (CPTP)、磷脂酰肌醇 4-磷酸衔接蛋白 2 (FAPP2)，其具有 GLTP 结构域和 GLTPD2。GLTP 超家族成员的体内功能作用已经慢慢显现。在这篇综述中，介绍并讨论了将人类 GLTP 超家族成员作为以下重要调节因子的最新进展：i ) 与 IV 组细胞质磷脂酶 A ₂相关的促炎类花生酸产生；ii ) 自噬和炎症小体组装，驱动监视细胞释放白细胞介素 1β 和白细胞介素 18 炎性细胞因子；三) 某些结肠癌细胞系中的细胞周期停滞和坏死性凋亡诱导。GLTP 超家族成员发挥的作用似乎与它们通过转运和/或传感器能力调节鞘脂稳态的能力有关。这些及时的发现为未来涉及人类健康和疾病中的 GLTP 折叠蛋白的跨学科、转化医学研究开辟了新途径。这些途径包括靶向调节特定的 GLTP 超家族成员以改变鞘脂水平，作为对抗病毒感染、神经退行性疾病和在癌症治疗期间规避化学抗性的治疗手段。