Galectin-4 Antimicrobial Activity Primarily Occurs Through its C-Terminal Domain.

IF 6.1 2区 生物学 Q1 BIOCHEMICAL RESEARCH METHODS Molecular & Cellular Proteomics Pub Date : 2024-05-01 Epub Date: 2024-03-13 DOI:10.1016/j.mcpro.2024.100747
Hau-Ming Jan, Shang-Chuen Wu, Carter J Stowell, Mary L Vallecillo-Zúniga, Anu Paul, Kashyap R Patel, Sasikala Muthusamy, Hsien-Ya Lin, Diyoly Ayona, Ryan Philip Jajosky, Samata P Varadkar, Hirotomo Nakahara, Rita Chan, Devika Bhave, William J Lane, Melissa Y Yeung, Marie A Hollenhorst, Seth Rakoff-Nahoum, Richard D Cummings, Connie M Arthur, Sean R Stowell
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Abstract

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.

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Galectin-4 的抗菌活性主要通过其 C 端结构域产生。
虽然免疫耐受的进化是为了降低与自身的反应性,但它却造成了适应性免疫反应的缺失,无法抵御用类似自身的抗原装饰自身的微生物。这一点在以碳水化合物为基础的血型抗原上表现得尤为明显,微生物可将自身包裹在与人体细胞相似的血型结构中。在这项研究中,我们证明了先天性免疫凝集素--galectin-4(Gal-4)对显示血型类抗原的微生物具有菌株特异性结合和杀伤行为。通过结合使用 ABO(H)聚糖的微阵列和多种微生物菌株(包括表达血型样抗原的微生物菌株)对其结合偏好的研究表明,Gal-4 能结合具有血型和哺乳动物样结构特征的哺乳动物和微生物抗原。尽管人们认为 Gal-4 是作为单体存在的,通过其两个相连的碳水化合物识别结构域(CRDs)实现功能上的双价性,但我们的数据表明 Gal-4 形成了二聚体,而且每个结构域二聚化的内在能力差异可能会影响结合亲和力。虽然每个 Gal-4 结构域都表现出血型结合活性,但 C 端结构域(Gal-4C)表现出二聚体特性,而 N 端结构域(Gal-4N)未能表现出类似的二聚体活性。Gal-4C 不仅具有二聚化能力,而且对 ABO(H)血型抗原和表达具有血型相似特征的聚糖的微生物具有更高的亲和力。此外,与 Gal-4N 相比,Gal-4C 表现出更强的抗菌活性。即使在全长蛋白质中,Gal-4N 通过 Gal-4C 二聚化而具有二价功能,Gal-4C 仍然显示出更高的抗菌活性。这些结果表明,Gal-4 是以二聚体形式存在的,主要通过其 C 端结构域表现出抗菌活性。因此,这些数据为我们深入了解 Gal-4 对抗分子拟态的先天免疫活性的关键特征提供了重要依据。
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来源期刊
Molecular & Cellular Proteomics
Molecular & Cellular Proteomics 生物-生化研究方法
CiteScore
11.50
自引率
4.30%
发文量
131
审稿时长
84 days
期刊介绍: The mission of MCP is to foster the development and applications of proteomics in both basic and translational research. MCP will publish manuscripts that report significant new biological or clinical discoveries underpinned by proteomic observations across all kingdoms of life. Manuscripts must define the biological roles played by the proteins investigated or their mechanisms of action. The journal also emphasizes articles that describe innovative new computational methods and technological advancements that will enable future discoveries. Manuscripts describing such approaches do not have to include a solution to a biological problem, but must demonstrate that the technology works as described, is reproducible and is appropriate to uncover yet unknown protein/proteome function or properties using relevant model systems or publicly available data. Scope: -Fundamental studies in biology, including integrative "omics" studies, that provide mechanistic insights -Novel experimental and computational technologies -Proteogenomic data integration and analysis that enable greater understanding of physiology and disease processes -Pathway and network analyses of signaling that focus on the roles of post-translational modifications -Studies of proteome dynamics and quality controls, and their roles in disease -Studies of evolutionary processes effecting proteome dynamics, quality and regulation -Chemical proteomics, including mechanisms of drug action -Proteomics of the immune system and antigen presentation/recognition -Microbiome proteomics, host-microbe and host-pathogen interactions, and their roles in health and disease -Clinical and translational studies of human diseases -Metabolomics to understand functional connections between genes, proteins and phenotypes
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