Niazi Ava, Kim Ju Ang, Kim Dong-Kyu, Lu Di, Sterin Igal, Park Joosang, Park Sungjin
Department of Neurobiology, University of Utah, Salt Lake City, UT, USA; Neuroscience Program, University of Utah, Salt Lake City, UT, USA.
Department of Neurobiology, University of Utah, Salt Lake City, UT, USA.
Dev Cell. 2025 Mar 10;60(5):679-695.e8. doi: 10.1016/j.devcel.2024.11.011. Epub 2024 Dec 9.
The apical extracellular matrix (aECM), organized by polarized epithelial cells, exhibits complex structures. The tectorial membrane (TM), an aECM in the cochlea mediating auditory transduction, exhibits highly ordered domain-specific architecture. α-Tectorin (TECTA), a glycosylphosphatidylinositol (GPI)-anchored ECM protein, is essential for TM organization. Here, we identified that α-tectorin is released by distinct modes: proteolytic shedding by TMPRSS2 and GPI-anchor-dependent release from the microvillus tip in mice. In the medial/limbal domain, proteolytically shed α-tectorin forms dense fibers. In contrast, in the lateral/body domain, where supporting cells exhibit dense microvilli, shedding restricts α-tectorin to the microvillus tip, compartmentalizing collagen-binding sites. Tip-localized α-tectorin is released in a GPI-anchor-dependent manner to form collagen-crosslinking fibers, maintaining the spacing and parallel organization of collagen fibrils. Overall, these distinct release modes of α-tectorin determine domain-specific organization, with the microvillus coordinating release modes along its membrane to assemble the higher-order ECM architecture.
由极化上皮细胞组织形成的顶端细胞外基质（aECM）呈现出复杂的结构。耳蜗中作为介导听觉转导的aECM的盖膜（TM），呈现出高度有序的结构域特异性结构。α-耳蜗蛋白（TECTA）是一种糖基磷脂酰肌醇（GPI）锚定的细胞外基质蛋白，对TM的组织至关重要。在这里，我们发现α-耳蜗蛋白通过不同的方式释放：在小鼠中通过跨膜丝氨酸蛋白酶2（TMPRSS2）进行蛋白水解切割以及从微绒毛尖端进行GPI锚定依赖性释放。在内侧/边缘结构域，蛋白水解切割的α-耳蜗蛋白形成致密纤维。相反，在外侧/主体结构域，支持细胞呈现密集的微绒毛，切割将α-耳蜗蛋白限制在微绒毛尖端，分隔胶原结合位点。尖端定位的α-耳蜗蛋白以GPI锚定依赖性方式释放以形成胶原交联纤维，维持胶原原纤维的间距和平行排列。总体而言，α-耳蜗蛋白的这些不同释放方式决定了结构域特异性组织，微绒毛沿其膜协调释放方式以组装高阶细胞外基质结构。
