Stabilization of F-actin by tropomyosin isoforms regulates the morphology and mechanical behavior of red blood cells.
Stabilization of F-actin by tropomyosin isoforms regulates the morphology and mechanical behavior of red blood cells.
复制标题
原肌球蛋白亚型对 F-肌动蛋白的稳定作用可调节红细胞的形态和机械行为。
DOI：
10.1091/mbc.e16-10-0699
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发表时间：
2017
影响因子：
3.3
通讯作者：
Fowler,VeliaM
中科院分区：
文献类型：
--
作者：
Sui,Zhenhua;Gokhin,DavidS;Nowak,RobertaB;Guo,Xinhua;An,Xiuli;Fowler,VeliaM
红细胞 (RBC) 膜骨架中的短 F-肌动蛋白沿其长度被两种原肌球蛋白亚型 Tpm1.9 和 Tpm3.1 的等摩尔组合所覆盖。我们假设原肌球蛋白稳定 F-肌动蛋白的能力可调节红细胞形态和机械特性。为了测试这一点，我们检查了 Tpm3 的选择性剪接外显子 9d (Tpm3/9d–/–) 中存在靶向缺失的小鼠，这导致红细胞中 Tpm3.1 缺失，同时 Tpm1.9 补偿性增加，其幅度足以维持正常的总原肌球蛋白含量。从 Tpm1.9/Tpm3.1 到仅 Tpm1.9 的异构体转换不会影响膜骨架组成，但会导致红细胞 F-肌动蛋白变得超稳定，这是基于对 latrunculin-A 诱导的解聚的脆弱性降低。出乎意料的是，这种亚型转换还导致带 3 和血型糖蛋白 A 与膜骨架的关联性降低，表明原肌球蛋白亚型调节 F-肌动蛋白与膜连接的强度。Tpm3/9d–/– 小鼠表现出轻度代偿性贫血，其中红细胞具有球形细胞形态，渗透脆性增加、膜变形性降低、膜稳定性增加。我们得出结论，红细胞原肌球蛋白亚型通过调节 1) 膜骨架中短 F-肌动蛋白的稳定性和 2) 膜骨架与跨膜糖蛋白之间的连接强度，直接影响红细胞生理学。
The short F-actins in the red blood cell (RBC) membrane skeleton are coated along their lengths by an equimolar combination of two tropomyosin isoforms, Tpm1.9 and Tpm3.1. We hypothesized that tropomyosin’s ability to stabilize F-actin regulates RBC morphology and mechanical properties. To test this, we examined mice with a targeted deletion in alternatively spliced exon 9d ofTpm3(Tpm3/9d–/–), which leads to absence of Tpm3.1 in RBCs along with a compensatory increase in Tpm1.9 of sufficient magnitude to maintain normal total tropomyosin content. The isoform switch from Tpm1.9/Tpm3.1 to exclusively Tpm1.9 does not affect membrane skeleton composition but causes RBC F-actins to become hyperstable, based on decreased vulnerability to latrunculin-A–induced depolymerization. Unexpectedly, this isoform switch also leads to decreased association of Band 3 and glycophorin A with the membrane skeleton, suggesting that tropomyosin isoforms regulate the strength of F-actin-to-membrane linkages.Tpm3/9d–/–mice display a mild compensated anemia, in which RBCs have spherocytic morphology with increased osmotic fragility, reduced membrane deformability, and increased membrane stability. We conclude that RBC tropomyosin isoforms directly influence RBC physiology by regulating 1) the stability of the short F-actins in the membrane skeleton and 2) the strength of linkages between the membrane skeleton and transmembrane glycoproteins.