Galectin-4 antimicrobial activity primarily occurs through its C-terminal domain.
Galectin-4 antimicrobial activity primarily occurs through its C-terminal domain.
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Galectin-4 抗菌活性主要通过其 C 末端结构域发生。
DOI：
10.1016/j.mcpro.2024.100747
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Lane,Wi
中科院分区：
文献类型：
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作者：
Jan,Hau-Ming;Wu,Shang-Chuen;Stowell,CarterJ;Vallecillo-Zúniga,MaryL;Paul,Anu;Patel,KashyapR;Muthusamy,Sasikala;Lin,Hsien-Ya;Ayona,Diyoly;Jajosky,RyanPhilip;Varadkar,SamataP;Nakahara,Hirotomo;Chan,Rita;Bhave,Devika;Lane,Wi
虽然免疫耐受的进化是为了减少与自身的反应，但它在适应性免疫反应中创造了一个缺口，以对抗以自身抗原装饰自己的微生物。这对于基于碳水化合物的血型抗原尤其明显，其中微生物可以将自身包裹在类似于人类细胞的血型结构中。在这项研究中，我们证明了先天免疫凝集素，半乳糖凝集素-4（Gal-4），对显示血型样抗原的微生物表现出菌株特异性结合和杀伤行为。使用含有ABO（H）聚糖和各种微生物菌株（包括表达血型样抗原的菌株）的微阵列组合进行结合偏好检查，证明Gal-4结合具有血型和类马克隆结构特征的哺乳动物和微生物抗原。虽然Gal-4被认为是通过其两个连接的碳水化合物识别结构域实现功能性二价的单体，但我们的数据表明Gal-4形成二聚体，并且每个结构域二聚化的内在能力的差异可能影响结合亲和力。虽然每个Gal-4结构域表现出血型结合活性，但C-末端结构域（Gal-4C）表现出二聚体性质，而N-末端结构域（Gal-4 N）未能类似地表现出二聚体活性。Gal-4C不仅表现出二聚化的能力，而且对ABO（H）血型抗原和表达具有血型样特征的聚糖的微生物具有更高的亲和力。此外，当与Gal-4 N相比时，Gal-4C表现出更有效的抗微生物活性。即使在全长蛋白的情况下，其中Gal-4 N由于Gal-4C二聚化而在功能上是二价的，Gal-4C继续显示出更高的抗微生物活性。这些结果表明，Gal-4作为二聚体存在，并主要通过其C-末端结构域表现出其抗微生物活性。在这样做的过程中，这些数据提供了重要的洞察Gal-4的关键特征，负责其对分子模拟的先天免疫活性。
Although immune tolerance evolved to reduce reactivity with self, it creates a gap in the adaptive immune response against microbes that decorate themselves in self-like antigens. This is particularly apparent with carbohydrate-based blood group antigens, wherein microbes can envelope themselves in blood group structures similar to human cells. In this study, we demonstrate that the innate immune lectin, galectin-4 (Gal-4), exhibits strain-specific binding and killing behavior towards microbes that display blood group–like antigens. Examination of binding preferences using a combination of microarrays populated with ABO(H) glycans and a variety of microbial strains, including those that express blood group–like antigens, demonstrated that Gal-4 binds mammalian and microbial antigens that have features of blood group and mammalian-like structures. Although Gal-4 was thought to exist as a monomer that achieves functional bivalency through its two linked carbohydrate recognition domains, our data demonstrate that Gal-4 forms dimers and that differences in the intrinsic ability of each domain to dimerize likely influences binding affinity. While each Gal-4 domain exhibited blood group–binding activity, the C-terminal domain (Gal-4C) exhibited dimeric properties, while the N-terminal domain (Gal-4N) failed to similarly display dimeric activity. Gal-4C not only exhibited the ability to dimerize but also possessed higher affinity toward ABO(H) blood group antigens and microbes expressing glycans with blood group–like features. Furthermore, when compared to Gal-4N, Gal-4C exhibited more potent antimicrobial activity. Even in the context of the full-length protein, where Gal-4N is functionally bivalent by virtue of Gal-4C dimerization, Gal-4C continued to display higher antimicrobial activity. These results demonstrate that Gal-4 exists as a dimer and exhibits its antimicrobial activity primarily through its C-terminal domain. In doing so, these data provide important insight into key features of Gal-4 responsible for its innate immune activity against molecular mimicry.