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Integrin binding site within the gC1q domain orchestrates EMILIN-1-induced lymphangiogenesis.
Matrix Biology ( IF 4.5 ) Pub Date : 2018-10-26 , DOI: 10.1016/j.matbio.2018.10.006
Alessandra Capuano 1 , Eliana Pivetta 1 , Francesca Baldissera 1 , Giulia Bosisio 1 , Bruna Wassermann 1 , Francesco Bucciotti 1 , Alfonso Colombatti 1 , Patrizia Sabatelli 2 , Roberto Doliana 1 , Paola Spessotto 1
Affiliation  

Lymphatic vessels (LVs) play a pivotal role in the control of tissue homeostasis and also have emerged as important regulators of immunity, inflammation and tumor metastasis. EMILIN-1 is the first ECM protein identified as a structural modulator of the growth and maintenance of LV; accordingly, Emilin1-/- mice display lymphatic morphological alterations leading to functional defects as mild lymphedema, leakage and compromised lymph drainage. Many EMILIN-1 functions are exerted by the binding of its gC1q domain with the E933 residue of α4 and α9β1 integrins. To investigate the specific regulatory role of this domain on lymphangiogenesis, we generated a transgenic mouse model expressing an E933A-mutated EMILIN-1 (E1-E933A), unable to interact with α4 or α9 integrin. The mutant resulted in abnormal LV architecture with dense, tortuous and irregular networks; moreover, the number of anchoring filaments was reduced and collector valves had aberrant narrowed structures. E933A mutation also affected lymphatic function in lymphangiography assays and made the transgenic mice more prone to lymph node metastases. The finding that the gC1q/integrin interaction is crucial for a correct lymphangiogenesis response was confirmed and reinforced by functional in vitro tubulogenesis assays. In addition, ex vivo thoracic-duct ring assays revealed that E1-E933A-derived lymphatic endothelial cells had a severe reduction in sprouting capacity and were unable to organize into capillary-like structures. All these data provide evidence that the novel "regulatory structural" role of EMILIN-1 in the lymphangiogenic process is played by the integrin binding site within its gC1q domain.

中文翻译:

gC1q域中的整联蛋白结合位点协调EMILIN-1诱导的淋巴管生成。

淋巴管(LVs)在组织动态平衡的控制中起着关键作用,并且已成为免疫,炎症和肿瘤转移的重要调节剂。EMILIN-1是第一个被鉴定为LV生长和维持的结构调节剂的ECM蛋白;因此,Emilin1-/-小鼠表现出淋巴形态改变,导致功能缺陷,如轻度淋巴水肿,渗漏和淋巴引流受损。EMILIN-1的许多功能是通过其gC1q结构域与α4和α9β1整联蛋白的E933残基结合而发挥的。为了研究该结构域在淋巴管生成中的特定调控作用,我们生成了表达E933A突变的EMILIN-1(E1-E933A)的转基因小鼠模型,该模型无法与α4或α9整联蛋白相互作用。该突变体导致左室结构异常,且致密,曲折和不规则的网络;此外,减少了锚定细丝的数量,并且集流阀具有异常狭窄的结构。E933A突变还影响淋巴管造影测定法中的淋巴功能,并使转基因小鼠更易于发生淋巴结转移。gC1q /整联蛋白相互作用对于正确的淋巴管生成反应至关重要,这一发现已通过功能性体外肾小管生成测定得到证实并得到了加强。另外,离体胸导管环测定法显示,E1-E933A来源的淋巴管内皮细胞的发芽能力严重降低,无法组织成毛细血管状结构。所有这些数据提供了新的“调节结构”的证据。
更新日期:2019-07-05
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