Institute of Molecular Biology and Medicinal Chemistry, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
Curr Med Chem. 2021;28(36):7387-7399. doi: 10.2174/0929867328666210215114140.
Mucous epithelia are protected by complex mucus barrier layers, which are part of the innate immune defense. Trefoil factor family peptides TFF1, TFF2, and TFF3 have lectin activities and are predominantly co-secreted together with mucins from these epithelia. TFF1 and TFF2 are mainly expressed in the gastric mucosa, whereas TFF3 is widely secreted from most mucous epithelia and their glands. TFF1 and TFF3 consist of a single TFF domain and an additional free 7th cysteine residue, whereas TFF2 contains two TFF domains. Systematic analyses of the molecular forms of TFFs gave new insights into their diverse molecular functions. TFF1 mainly exists as a monomer with an unusual free thiol group and only minor amounts form a disulfide-linked homodimer as well as heterodimers with gastrokine-2 and IgG-Fc-binding protein (FCGBP). TFF3 mainly forms a heterodimer with FCGBP in vivo, but also binds Deleted in Malignant Brain Tumors/gp340 (DMBT1) in vitro. In contrast, TFF2 binds as a lectin to a conserved O-linked carbohydrate moiety of the mucin MUC6. Both FCGBP and DMBT1 are secreted by most mucous epithelia and their glands and are involved in mucosal innate immunity. Thus, a new picture emerged pointing to functions of TFF3-FCGBP (and TFF1-FCGBP) for mucosal innate immune defense, e.g. supporting the clearing of the microorganisms. Such a function could be well be supported by DMBT1. In contrast, the TFF2/MUC6 lectin complex probably physically stabilizes the inner adherent gastric mucus layer. Furthermore, there are indications that TFF3- FCGBP might also play a role in the blood vessels.
黏膜上皮由复杂的黏液屏障层保护，该屏障层是先天免疫防御的一部分。三叶因子家族肽 TFF1、TFF2 和 TFF3 具有凝集素活性，主要与这些上皮细胞的黏蛋白共同被分泌。TFF1 和 TFF2 主要在胃黏膜中表达，而 TFF3 则广泛分泌自大多数黏液上皮及其腺体。TFF1 和 TFF3 由单个 TFF 结构域和另一个额外的游离第 7 个半胱氨酸残基组成，而 TFF2 则包含两个 TFF 结构域。对 TFF 分子形式的系统分析为其多种分子功能提供了新的见解。TFF1 主要以单体形式存在，具有异常的游离巯基基团，只有少量形成二硫键连接的同源二聚体以及与胃泌素-2 和 IgG-Fc 结合蛋白 (FCGBP) 的异源二聚体。TFF3 主要在体内与 FCGBP 形成异源二聚体，但也在体外与Deleted in Malignant Brain Tumors/gp340 (DMBT1) 结合。相比之下，TFF2 作为凝集素与黏蛋白 MUC6 的保守 O-连接糖基部分结合。FCGBP 和 DMBT1 均由大多数黏液上皮及其腺体分泌，并参与黏膜先天免疫。因此，出现了一个新的观点，即 TFF3-FCGBP（和 TFF1-FCGBP）在黏膜先天免疫防御中的功能，例如支持清除微生物。DMBT1 很可能支持这种功能。相反，TFF2/MUC6 凝集素复合物可能在物理上稳定内层黏附性胃黏液层。此外，有迹象表明 TFF3-FCGBP 也可能在血管中发挥作用。
