A glycoprotein in urine binds bacteria and blocks infections

doi:10.1126/science.abd7124

GSTDTAP > 气候变化

DOI	10.1126/science.abd7124
	A glycoprotein in urine binds bacteria and blocks infections
	Wanda Kukulski
	2020-08-21
发表期刊	Science
出版年	2020
英文摘要	Human urinary tracts are highly susceptible to bacterial infections. Pathogenic bacteria initiate infections by attaching to sugar chains (glycans) exposed on the surface of the urinary tract epithelium ([ 1 ][1]). It has long been suspected that uromodulin (UMOD)—the most abundant protein in human urine—prevents bacteria from binding to urinary tract glycans, thus defending the organism from such infections ([ 2 ][2]). However, the mechanism underlying this protection has remained elusive. Now, on page 1005 of this issue, Weiss et al. reveal, at the molecular level, how UMOD filaments interact with uropathogenic Escherichia coli cells in human urine ([ 3 ][3]). These results provide a structural basis for understanding the protective function of UMOD. UMOD forms filaments first visualized by electron microscopy more than 60 years ago ([ 4 ][4]). Despite these early images, the filaments' structural organization is unknown, which is, in part, why the protective role of UMOD has eluded scientists. An important hint regarding UMOD function came from the fact that myriad glycans decorate the filaments, possibly presenting bacteria with binding opportunities that compete with glycan receptors on the urinary tract walls ([ 5 ][5]). Weiss et al. deciphered a comprehensive map of the glycosylation pattern of UMOD, the structure of UMOD filaments, and the nature of bacteria–filament interaction. Infective E. coli cells attach to the urinary tract epithelium through needlelike structures called pili. At their tip, E. coli type I pili consist of the protein FimH (type 1 fimbrin d-mannose specific adhesin) ([ 6 ][6]). The authors show that the armlike structures extending from UMOD filaments interact with FimH. The interaction between UMOD and FimH is biochemically strong and likely leads to stable binding. Indeed, Weiss et al. show that through this binding, UMOD mediates the stable formation of clumps of bacteria. The suggested mechanism of UMOD-based defense is notably simple and robust: The abundant UMOD filaments outcompete receptors on the urinary tract walls in binding to bacterial pili. Each flexible filament has multiple binding sites, and each bacterium can have several pili. Therefore, this multitude of interactions causes bacterial aggregation, effectively preventing individual bacterial cells from attaching to and infecting the urinary tract. In case of the E. coli strain studied by Weiss et al. , the interaction between UMOD and bacterial cells occurs through specific binding of FimH to a glycan at asparagine 275 of the UMOD protein (see the figure). ![Figure][7] Filaments fight infection Uromodulin (UMOD) forms filaments that compete with the adhesion of uropathogens to the urinary tract epithelium. By binding to bacterial pili, UMOD filaments corral uropathogens, block bacterial adhesion in the urinary tract, and permit pathogen clearance through urination. FimH, type 1 fimbrin d-mannose specific adhesin. GRAPHIC: JOSHUA BIRD/ SCIENCE However, UMOD contains several other complex glycosylation sites whose functions have not yet been dissected. A compelling possibility is that these serve as binding sites for proteins of other uropathogenic bacteria. In line with this idea, when Weiss et al. imaged urine from patients infected with different bacteria, namely Klebsiella, Pseudomonas , and Streptococcus , the authors found similarly aggregated bacterial cells embedded in UMOD filaments. Given its implication in various aspects of kidney function ([ 7 ][8]), UMOD might have other molecular roles that rely on its distinct glycosylation pattern or its adoption of a filamentous structure, besides protection from bacterial infections. What has enabled this breakthrough in understanding of the association between UMOD and uropathogenic bacteria? The careful and systematic mass spectrometry data for the glycosylation map laid the foundation for resolving this mystery. The key, however, was the integration of these data with cryo–electron tomography (cryo-ET). This electron microscopy (EM)–based method allows one to visualize three-dimensional architectures of near-natively preserved samples at a resolution high enough to see individual macromolecules. Cryo-ET can be applied to samples that are too irregular, large, or heterogenous for cryo-EM, which allows cryo-ET to span the range from purified samples to complex reconstitutions with diverse components and even undisturbed cellular samples. Similar to cryo-EM data, cryo-ET data can be processed by averaging structures in subvolumes, thereby further increasing the resolution ([ 8 ][9]). Whereas cryo-EM is currently revolutionizing structural biology by visualizing protein structures at atomic resolution ([ 9 ][10]), cryo-ET lags behind in terms of resolution, although for certain structures a resolution better than 5 Å can be achieved ([ 10 ][11], [ 11 ][12]). A singular asset of cryo-ET, however, is its ability to seamlessly investigate a structure across multiple scales of complexity. The power of this approach is demonstrated impressively in this study. The authors used cryo-ET followed by subtomogram averaging to determine the architecture of purified native UMOD filaments and the interaction region between UMOD filaments and FimH. They also used cryo-ET to image the binding of bacterial cells to UMOD. The visualization of entangled bacteria is particularly notable, as it involved direct imaging of unprocessed urine from patients diagnosed with urinary tract infections. Although cryo-ET continues to provide unprecedented views of large macromolecular assemblies and cellular architecture ([ 12 ][13], [ 13 ][14]), its application to primary samples of human origin is thus far scarce ([ 14 ][15]). The approach taken by Weiss et al. —to assess the molecular basis of disease by directly imaging a human fluid—is conceptually simple, yet represents a milestone by demonstrating the potential of cryo-ET for biomedical imaging. Future studies likely will expand the use of cryo-ET to explore fundamental questions on the role of supramolecular architecture in human health and disease. 1. [↵][16]1. G. Zhou et al ., J. Cell Sci. 114, 4095 (2001). [OpenUrl][17][Abstract/FREE Full Text][18] 2. [↵][19]1. F. Serafini-Cessi, 2. A. Monti, 3. D. Cavallone , Glycoconj. J. 22, 383 (2005). [OpenUrl][20][CrossRef][21][PubMed][22][Web of Science][23] 3. [↵][24]1. G. L. Weiss et al ., Science 369, 1005 (2020). [OpenUrl][25][Abstract/FREE Full Text][26] 4. [↵][27]1. K. R. 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/291203
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Wanda Kukulski. A glycoprotein in urine binds bacteria and blocks infections[J]. Science,2020.
APA	Wanda Kukulski.(2020).A glycoprotein in urine binds bacteria and blocks infections.Science.
MLA	Wanda Kukulski."A glycoprotein in urine binds bacteria and blocks infections".Science (2020).