Institute of Biochemistry I, Jena University Hospital - Friedrich Schiller University Jena, 07743 Jena, Germany.
Biochem Soc Trans. 2020 Feb 28;48(1):137-146. doi: 10.1042/BST20190377.
The formation of caveolae, bulb-shaped plasma membrane invaginations, requires the coordinated action of distinct lipid-interacting and -shaping proteins. The interdependence of caveolar structure and function has evoked substantial scientific interest given the association of human diseases with caveolar dysfunction. Model systems deficient of core components of caveolae, caveolins or cavins, did not allow for an explicit attribution of observed functional defects to the requirement of caveolar invagination as they lack both invaginated caveolae and caveolin proteins. Knockdown studies in cultured cells and recent knockout studies in mice identified an additional family of membrane-shaping proteins crucial for caveolar formation, syndapins (PACSINs) - BAR domain superfamily proteins characterized by crescent-shaped membrane binding interfaces recognizing and inducing distinct curved membrane topologies. Importantly, syndapin loss-of-function resulted exclusively in impairment of caveolar invagination without a reduction in caveolin or cavin at the plasma membrane, thereby allowing the specific role of the caveolar invagination to be unveiled. Muscle cells of syndapin III KO mice showed severe reductions of caveolae reminiscent of human caveolinopathies and were more vulnerable to membrane damage upon changes in membrane tensions. Consistent with the lack of syndapin III-dependent invaginated caveolae providing mechanoprotection by releasing membrane reservoirs through caveolar flattening, physical exercise of syndapin III KO mice resulted in pathological defects reminiscent of the clinical symptoms of human myopathies associated with caveolin 3 mutation suggesting that the ability of muscular caveolae to respond to mechanical forces is a key physiological process.
小窝形成，即质膜凹陷的泡状结构，需要不同的脂类相互作用和塑形蛋白共同协调作用。鉴于小窝功能障碍与人类疾病之间的关联，小窝的结构和功能的相互依赖性引起了广泛的科学关注。小窝的核心成分（窖蛋白或窖脂素）缺失的模型系统，由于缺乏凹陷的小窝和窖蛋白，无法明确将观察到的功能缺陷归因于小窝凹陷的需求。在培养细胞中的敲低研究和最近在小鼠中的敲除研究，鉴定了另一类对小窝形成至关重要的膜塑形蛋白，衔接蛋白（衔接蛋白家族小 GTP 酶激活蛋白）- BAR 结构域超家族蛋白，其特征为新月形的膜结合界面，识别并诱导不同的弯曲膜拓扑结构。重要的是，衔接蛋白功能丧失仅导致小窝凹陷受损，而质膜上的窖蛋白或窖脂素没有减少，从而可以揭示小窝凹陷的特定作用。衔接蛋白 III KO 小鼠的肌肉细胞中，小窝明显减少，使人联想到人类的窖蛋白病，并且在膜张力变化时更容易受到膜损伤。与缺乏依赖衔接蛋白 III 的凹陷小窝通过小窝变平释放膜储库提供机械保护一致，衔接蛋白 III KO 小鼠的体力活动导致病理缺陷，使人联想到与窖蛋白 3 突变相关的人类肌病的临床症状，这表明肌肉小窝对机械力的反应能力是一个关键的生理过程。
