Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Curr Biol. 2018 Sep 24;28(18):2876-2888.e4. doi: 10.1016/j.cub.2018.07.022. Epub 2018 Sep 6.
Transporting epithelial cells like those that line the gut build large arrays of actin-supported protrusions called microvilli, which extend from the apical surface into luminal spaces to increase functional surface area. Although critical for maintaining physiological homeostasis, mechanisms controlling the formation of microvilli remain poorly understood. Here, we report that the inverse-bin-amphiphysin-Rvs (I-BAR)-domain-containing protein insulin receptor tyrosine kinase substrate (IRTKS) (also known as BAIAP2L1) promotes the growth of epithelial microvilli. Super-resolution microscopy and live imaging of differentiating epithelial cells revealed that IRTKS localizes to the distal tips of actively growing microvilli via a mechanism that requires its N-terminal I-BAR domain. At microvillar tips, IRTKS promotes elongation through a mechanism involving its C-terminal actin-binding WH2 domain. IRTKS can also drive microvillar elongation using its SH3 domain to recruit the bundling protein EPS8 to microvillar tips. These results provide new insight on mechanisms that control microvillar growth during the differentiation of transporting epithelial cells and help explain why IRTKS is targeted by enteric pathogens that disrupt microvillar structure during infection of the intestinal epithelium.
将像肠道衬里那样的上皮细胞运输到细胞中，会构建大量由肌动蛋白支撑的突起，称为微绒毛，这些突起从顶端表面延伸到腔隙中，以增加功能表面积。尽管这对于维持生理内稳态至关重要，但控制微绒毛形成的机制仍知之甚少。在这里，我们报告说，含有反向二聚体结构域的胰岛素受体酪氨酸激酶底物（IRTKS）（也称为 BAIAP2L1）蛋白促进上皮细胞微绒毛的生长。超分辨率显微镜和分化上皮细胞的实时成像显示，IRTKS 通过一种需要其 N 端 I-BAR 结构域的机制定位于活跃生长的微绒毛的远端尖端。在微绒毛尖端，IRTKS 通过其 C 端肌动蛋白结合 WH2 结构域促进伸长。IRTKS 还可以通过其 SH3 结构域驱动微绒毛伸长，将束状蛋白 EPS8 募集到微绒毛尖端。这些结果为控制运输上皮细胞分化过程中微绒毛生长的机制提供了新的见解，并有助于解释为什么 IRTKS 是肠道病原体的靶点，这些病原体在感染肠道上皮细胞时会破坏微绒毛结构。
