Interphotoreceptor matrix proteoglycans IMPG1 and IMPG2 proteolyze in the SEA domain and reveal localization mutual dependency.
Interphotoreceptor matrix proteoglycans IMPG1 and IMPG2 proteolyze in the SEA domain and reveal localization mutual dependency.
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DOI：
10.1038/s41598-022-19910-1
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发表时间：
2022-09-15
影响因子：
4.6
通讯作者：
Salido, Ezequiel M.
中科院分区：
文献类型：
--
作者：
Mitchell, Benjamin;Coulter, Chloe;Geldenhuys, Werner J.;Rhodes, Scott;Salido, Ezequiel M.
光感受器间基质(IPM)是围绕光感受器神经元内外节段的一种特殊的细胞外分子网。光受体基质蛋白多糖1和2(IMPG1和IMPG2)是IPM的主要成分。这两种蛋白多糖都含有SEA(精子蛋白、肠激酶和集聚蛋白)结构域，可能支持蛋白降解。有趣的是，IMPG1和IMPG2海区的突变与人类的视力疾病有关。然而，IMPG分子中的SEA结构域是否发生蛋白质分解，以及这如何促进视觉病理尚不清楚。因此，我们研究了SEA介导的IMPG1和IMPG2的蛋白分解及其对IPM生理学的意义。免疫印迹分析证实了野生型小鼠视网膜中IMPG1和IMPG2的蛋白降解。与视力疾病相关的IMPG1海域中模仿人类突变的点突变抑制了蛋白质分解。这些发现表明，蛋白分解是IMPG1和IMPG2成熟的一部分，而IMPG1和IMPG2的缺陷与视力疾病有关。此外，免疫组织化学分析表明，IMPG2的蛋白分解产生了两个亚单位，一个是膜附着肽，一个是胞外肽。值得注意的是，IMPG2的胞外部分通过依赖于IMPG1的机制从内段周围的IPM流向外段IPM。这一结果首次提供了贩运系统以相互依赖的方式将IMPG1和IMPG2从内部IPM运送到外部IPM的证据。此外，这些结果提示了IMPG1-IMPG2之间的相互作用，并提出影响一个IMPG的突变可能会影响正常IMPG伴侣的定位，从而导致与IMPG分子缺陷相关的视力疾病的发病机制。
The interphotoreceptor matrix (IPM) is a specialized extracellular mesh of molecules surrounding the inner and outer segments of photoreceptor neurons. Interphotoreceptor matrix proteoglycan 1 and 2 (IMPG1 and IMPG2) are major components of the IPM. Both proteoglycans possess SEA (sperm protein, enterokinase and agrin) domains, which may support proteolysis. Interestingly, mutations in the SEA domains of IMPG1 and IMPG2 are associated with vision disease in humans. However, if SEA domains in IMPG molecules undergo proteolysis, and how this contributes to vision pathology is unknown. Therefore, we investigated SEA-mediated proteolysis of IMPG1 and IMPG2 and its significance to IPM physiology. Immunoblot analysis confirmed proteolysis of IMPG1 and IMPG2 in the retinas of wildtype mice. Point mutations mimicking human mutations in the SEA domain of IMPG1 that are associated with vision disease inhibited proteolysis. These findings demonstrate that proteolysis is part of the maturation of IMPG1 and IMPG2, in which deficits are associated with vision diseases. Further, immunohistochemical assays showed that proteolysis of IMPG2 generated two subunits, a membrane-attached peptide and an extracellular peptide. Notably, the extracellular portion of IMPG2 trafficked from the IPM around the inner segment toward the outer segment IPM by an IMPG1-dependent mechanism. This result provides the first evidence of a trafficking system that shuttles IMPG1 and IMPG2 from the inner to outer IPM in a co-dependent manner. In addition, these results suggest an interaction between IMPG1–IMPG2 and propose that mutations affecting one IMPG could affect the localization of the normal IMPG partner, contributing to the disease mechanism of vision diseases associated with defective IMPG molecules.
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影响因子：
9.8
作者：
Bandah-Rozenfeld, Dikla;Collin, Rob W. J.;den Hollander, Anneke I.
通讯作者：
den Hollander, Anneke I.
DOI：
10.1006/mcbr.1999.0161
发表时间：
1999-08-01
期刊：
Molecular cell biology research communications : MCBRC
影响因子：
--
作者：
Kuehn, M H;Hageman, G S
通讯作者：
Hageman, G S
DOI：
10.1016/j.bbapap.2020.140361
发表时间：
2020-03-01
影响因子：
3.2
作者：
Noguera，Martin E.;Jakoncic，Jean;Ermacora，Mario R.
通讯作者：
Ermacora，Mario R.
影响因子：
17.8
作者：
Chowers, Itay;Tiosano, Liran;Boon, Camiel J. F.
通讯作者：
Boon, Camiel J. F.
影响因子：
9.8
作者：
Manes, Gael;Meunier, Isabelle;Hamel, Christian P.
通讯作者：
Hamel, Christian P.