Fibrillin microfibrils play a critical role in the formation of elastic fibers, tissue/organ development, and cardiopulmonary function. These microfibrils not only provide structural support and flexibility to tissues, but they also regulate growth factor signaling through a plethora of microfibril-binding proteins in the extracellular space. Mutations in fibrillins are associated with human diseases affecting cardiovascular, pulmonary, skeletal, and ocular systems. Fibrillins consist of up to 47 epidermal growth factor-like repeats, of which more than half are modified by protein -glucosyltransferase 2 (POGLUT2) and/or POGLUT3. Loss of these modifications reduces secretion of N-terminal fibrillin constructs overexpressed Here, we investigated the role of POGLUT2 and POGLUT3 using a double knockout mouse model. Blocking glucosylation caused neonatal death with skeletal, pulmonary, and eye defects reminiscent of fibrillin/elastin mutations. Proteomic analyses of dermal fibroblast medium and extracellular matrix provided evidence that fibrillins were more sensitive to loss of -glucose compared to other POGLUT2/3 substrates. This conclusion was supported by immunofluorescent analyses of late gestation lungs where FBN levels were reduced and microfibrils appeared fragmented in the pulmonary arteries and veins, bronchioles, and developing saccules. Defects in fibrillin microfibrils likely contributed to impaired elastic fiber formation and histological changes observed in lung blood vessels, bronchioles, and saccules. Collectively, these results highlight the importance of POGLUT2/3-mediated -glucosylation and open the possibility that glucose modifications on fibrillin influence microfibril assembly and or protein interactions in the ECM environment.

中文翻译：

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Poglut2/3 双敲除小鼠导致新生儿死亡，肺组织中原纤维蛋白水平降低


原纤维蛋白微纤维在弹性纤维的形成、组织/器官发育和心肺功能中发挥着关键作用。这些微原纤维不仅为组织提供结构支撑和灵活性，而且还通过细胞外空间中的大量微原纤维结合蛋白调节生长因子信号传导。原纤维蛋白突变与影响心血管、肺、骨骼和眼系统的人类疾病有关。原纤维蛋白由多达 47 个表皮生长因子样重复序列组成，其中一半以上被蛋白-葡萄糖基转移酶 2 (POGLUT2) 和/或 POGLUT3 修饰。这些修饰的丢失会减少过度表达的 N 端原纤维蛋白构建体的分泌在此，我们使用双敲除小鼠模型研究了 POGLUT2 和 POGLUT3 的作用。阻断糖基化会导致新生儿死亡，并伴有骨骼、肺部和眼睛缺陷，让人想起原纤维蛋白/弹性蛋白突变。真皮成纤维细胞培养基和细胞外基质的蛋白质组学分析提供的证据表明，与其他 POGLUT2/3 底物相比，原纤维蛋白对 β-葡萄糖的损失更敏感。这一结论得到了对妊娠晚期肺部的免疫荧光分析的支持，其中 FBN 水平降低，肺动脉和静脉、细支气管和发育中的球囊中的微纤维出现碎片。原纤维蛋白微原纤维的缺陷可能导致弹性纤维形成受损以及在肺血管、细支气管和球囊中观察到的组织学变化。总的来说，这些结果强调了 POGLUT2/3 介导的葡萄糖基化的重要性，并提出了原纤维蛋白上的葡萄糖修饰影响 ECM 环境中微原纤维组装和/或蛋白质相互作用的可能性。