Functional and structural analyses reveal that a dual domain sialidase protects bacteria from complement killing through desialylation of complement factors.
Functional and structural analyses reveal that a dual domain sialidase protects bacteria from complement killing through desialylation of complement factors.
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DOI：
10.1371/journal.ppat.1011674
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发表时间：
2023-09
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
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补体系统是抵御微生物感染的第一道天然免疫防线。为了在人类体内生存并引起感染，细菌病原体已经开发出复杂的机制来破坏补体介导的杀菌活性。有报道称唾液酸酶，也称为神经氨酸酶，与细菌补体耐药有关；然而，其潜在的分子机制仍不清楚。几种补体蛋白(例如C1q、C4和C5)和调节因子(例如因子H和C4BP)被各种唾液酸聚糖(末端含唾液酸的多糖)修饰，这些唾液酸聚糖对它们的功能是必不可少的。这份报告提供了功能和结构上的证据，证明细菌唾液酸酶可以通过分析关键的补体蛋白和调节因子来解除补体系统的武装。牙龈卟啉单胞菌是牙周炎的“基石”病原菌，它产生一种双域唾液酸酶(PG0352)。生化分析表明，PG0352可抑制人血清和补体因子，从而保护细菌免受血清杀灭。结构分析表明，PG0352含有一个N-末端糖类结合模块和一个C-末端唾液酸酶结构域，每个叶片由3-4条反平行的β链组成。后续功能研究表明，PG0352形成单体，在较宽的pH范围内具有活性。虽然PG0352可以去除N-乙酰神经氨酸(Neu5Ac)和N-乙醇基神经氨酸(Neu5Gc)，但它对人类最丰富的唾液酸Neu5Ac有更高的亲和力。结构和功能分析进一步证明，CBM与碳水化合物和血清糖蛋白结合。这份报告的结果为理解唾液酸酶在细菌毒力中的作用提供了新的见解，并为研究细菌补体耐药性的分子机制开辟了一条新的途径。人类补体途径是一种高效的识别和效应系统，致力于摧毁感染性微生物和受损的宿主物质，因此被认为是天然免疫防御的第一线。细菌病原体已经进化出各种策略来逃避补体系统并导致感染。补体耐药机制可以作为新的治疗靶点，用于预防高度耐药的病原菌感染，包括牙周炎，一种由多菌感染引发的慢性炎症性疾病。因此，了解补体系统和细菌病原体之间的相互作用对于开发治疗包括牙周炎在内的细菌感染的新疗法至关重要。细菌唾液酸酶已被报道与补体耐药有关，但其潜在机制在很大程度上仍不清楚。这份报告揭示了唾液酸酶通过分析关键补体蛋白和调节因子来增强细菌对补体的抵抗力，这可能成为治疗传染病的新的治疗靶点。
The complement system is the first line of innate immune defense against microbial infections. To survive in humans and cause infections, bacterial pathogens have developed sophisticated mechanisms to subvert the complement-mediated bactericidal activity. There are reports that sialidases, also known as neuraminidases, are implicated in bacterial complement resistance; however, its underlying molecular mechanism remains elusive. Several complement proteins (e.g., C1q, C4, and C5) and regulators (e.g., factor H and C4bp) are modified by various sialoglycans (glycans with terminal sialic acids), which are essential for their functions. This report provides both functional and structural evidence that bacterial sialidases can disarm the complement system via desialylating key complement proteins and regulators. The oral bacterium Porphyromonas gingivalis, a “keystone” pathogen of periodontitis, produces a dual domain sialidase (PG0352). Biochemical analyses reveal that PG0352 can desialylate human serum and complement factors and thus protect bacteria from serum killing. Structural analyses show that PG0352 contains a N-terminal carbohydrate-binding module (CBM) and a C-terminal sialidase domain that exhibits a canonical six-bladed β-propeller sialidase fold with each blade composed of 3–4 antiparallel β-strands. Follow-up functional studies show that PG0352 forms monomers and is active in a broad range of pH. While PG0352 can remove both N-acetylneuraminic acid (Neu5Ac) and N-glycolyl-neuraminic acid (Neu5Gc), it has a higher affinity to Neu5Ac, the most abundant sialic acid in humans. Structural and functional analyses further demonstrate that the CBM binds to carbohydrates and serum glycoproteins. The results shown in this report provide new insights into understanding the role of sialidases in bacterial virulence and open a new avenue to investigate the molecular mechanisms of bacterial complement resistance. The human complement pathway is a highly efficient recognition and effector system dedicated to destroy infectious microbes and damaged host materials and thus it has been considered as the first line of innate immune defense. Bacterial pathogens have evolved various tactics to evade the complement system and cause infections. Complement resistance mechanisms can serve as novel therapeutic targets for defending against highly antibiotic-resistant pathogenic bacterial infections, including periodontitis, a chronic inflammatory illness that is triggered by polymicrobial infection. Therefore, understanding the interplay between the complement system and bacterial pathogens is critical for developing new therapeutics against bacterial infections including periodontitis. Bacterial sialidases have been reported to be implicated in complement resistance, and yet its underlying mechanism remains largely unknown. This report reveals that sialidases confer bacteria complement resistance via desialylating key complement proteins and regulators, which can potentially serve as a new therapeutic target for treatment of infectious diseases.
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影响因子：
14.9
作者：
Drula E;Garron ML;Dogan S;Lombard V;Henrissat B;Terrapon N
通讯作者：
Terrapon N
DOI：
10.1107/s2053230x23001735
发表时间：
2023-04-01
影响因子：
0.9
作者：
Dong, Wen-Bo;Jiang, Yong-Liang;Zhou, Kang
通讯作者：
Zhou, Kang
影响因子：
5.7
作者：
CRENNELL, S;GARMAN, E;TAYLOR, G
通讯作者：
TAYLOR, G
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
2.8
作者：
Frey, Andrew M.;Satur, Marianne J.;Stafford, Graham
通讯作者：
Stafford, Graham