CLIC4 调节 RPE 细胞粘着斑处 MMP14 的晚期内体运输和基质降解活性。,Scientific Reports

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CLIC4 调节 RPE 细胞粘着斑处 MMP14 的晚期内体运输和基质降解活性。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-08-22 , DOI: 10.1038/s41598-019-48438-0
Kuo-Shun Hsu _{1,

2} , Wataru Otsu _{1,

3} , Yao Li ₄ , Heuy-Ching Wang ₅ , Shuibing Chen ₆ , Stephen H Tsang _{4,

7,

8,

9} , Jen-Zen Chuang ₁ , Ching-Hwa Sung _{1,

10}

Affiliation

Department of Ophthalmology, Weill Medical College of Cornell University, New York, NY, USA.
Department of Surgery, Colorectal Service and Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Biomedical Research Laboratory, Gifu Pharmaceutical University, Gifu, Japan.
Department of Ophthalmology, Columbia University, New York, NY, USA.
Ocular Trauma Task Area, US Army Institute of Surgical Research, Joint Base San Antonio-Fort Sam Houston, TX, San Antonio, USA.
Department of Surgery and Department of Biochemistry, Weill Medical College of Cornell University, New York, NY, USA.
Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
Department of Pathology & Cell Biology, and Columbia Stem Cell Initiative, Columbia University Medical Center, New York, NY, USA.
Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA.

视网膜色素上皮 (RPE) 周围细胞外基质 (ECM) 微环境的失调与增殖性玻璃体视网膜病变和年龄相关性黄斑变性的病因有关。RPE 细胞对 ECM 重塑的调控尚不清楚。我们表明膜型基质金属蛋白酶 14 (MMP14) 是人 ARPE19 细胞粘着斑处 ECM 降解的核心。粘着斑的基质降解活性而非组装受氯细胞内通道 4 (CLIC4) 调节。CLIC4 在晚期核内体中与 MMP14 共定位。CLIC4 调节 MMP14 正确分选到晚期内体的腔内及其在脂筏中的蛋白水解激活。CLIC4 具有新发现的“晚期结构域”基序，可与 MMP14 和 Tsg101 结合，运输所需的内体分选复合体 (ESCRT) 复合体的一个组成部分。与晚期结构域突变体 CLIC4 不同，野生型 CLIC4 可以挽救 MMP14 的晚期内体分选缺陷。最后，CLIC4 敲低抑制了极化人 RPE 单层中 MMP2 的顶端分泌。这些结果综合起来表明，CLIC4 是一种新型基质微环境调节剂，也是一种用于晚期内体货物分选的新型调节剂。此外，MMP14 的晚期内体分选积极调节其在 RPE 细胞中的表面活化。证明 CLIC4 是一种新型基质微环境调节剂和一种用于晚期内体货物分选的新型调节剂。此外，MMP14 的晚期内体分选积极调节其在 RPE 细胞中的表面活化。证明 CLIC4 是一种新型基质微环境调节剂和一种用于晚期内体货物分选的新型调节剂。此外，MMP14 的晚期内体分选积极调节其在 RPE 细胞中的表面活化。

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CLIC4 regulates late endosomal trafficking and matrix degradation activity of MMP14 at focal adhesions in RPE cells.

Dysregulation in the extracellular matrix (ECM) microenvironment surrounding the retinal pigment epithelium (RPE) has been implicated in the etiology of proliferative vitreoretinopathy and age-related macular degeneration. The regulation of ECM remodeling by RPE cells is not well understood. We show that membrane-type matrix metalloproteinase 14 (MMP14) is central to ECM degradation at the focal adhesions in human ARPE19 cells. The matrix degradative activity, but not the assembly, of the focal adhesion is regulated by chloride intracellular channel 4 (CLIC4). CLIC4 is co-localized with MMP14 in the late endosome. CLIC4 regulates the proper sorting of MMP14 into the lumen of the late endosome and its proteolytic activation in lipid rafts. CLIC4 has the newly-identified "late domain" motif that binds to MMP14 and to Tsg101, a component of the endosomal sorting complex required for transport (ESCRT) complex. Unlike the late domain mutant CLIC4, wild-type CLIC4 can rescue the late endosomal sorting defect of MMP14. Finally, CLIC4 knockdown inhibits the apical secretion of MMP2 in polarized human RPE monolayers. These results, taken together, demonstrate that CLIC4 is a novel matrix microenvironment modulator and a novel regulator for late endosomal cargo sorting. Moreover, the late endosomal sorting of MMP14 actively regulates its surface activation in RPE cells.

更新日期：2019-08-22

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