NUMB 功能障碍定义了高尿酸血症和痛风的新机制。

IF 13 1区 生物学 Q1 CELL BIOLOGY
Jingwei Chi, Ying Chen, Changgui Li, Shiguo Liu, Kui Che, Zili Kong, Ziheng Guo, Yanchen Chu, Yajing Huang, Libo Yang, Cunwei Sun, Yunyang Wang, Wenshan Lv, Qing Zhang, Hui Guo, Han Zhao, Zhitao Yang, Lili Xu, Ping Wang, Bingzi Dong, Jianxia Hu, Shihai Liu, Fei Wang, Yanyun Zhao, Mengmeng Qi, Yu Xin, Huiqi Nan, Xiangzhong Zhao, Wei Zhang, Min Xiao, Ke Si, Yangang Wang, Yihai Cao
{"title":"NUMB 功能障碍定义了高尿酸血症和痛风的新机制。","authors":"Jingwei Chi, Ying Chen, Changgui Li, Shiguo Liu, Kui Che, Zili Kong, Ziheng Guo, Yanchen Chu, Yajing Huang, Libo Yang, Cunwei Sun, Yunyang Wang, Wenshan Lv, Qing Zhang, Hui Guo, Han Zhao, Zhitao Yang, Lili Xu, Ping Wang, Bingzi Dong, Jianxia Hu, Shihai Liu, Fei Wang, Yanyun Zhao, Mengmeng Qi, Yu Xin, Huiqi Nan, Xiangzhong Zhao, Wei Zhang, Min Xiao, Ke Si, Yangang Wang, Yihai Cao","doi":"10.1038/s41421-024-00708-6","DOIUrl":null,"url":null,"abstract":"<p><p>Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMB<sup>R630H</sup>) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMB<sup>R630H</sup> knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMB<sup>R630H</sup> knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"106"},"PeriodicalIF":13.0000,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494200/pdf/","citationCount":"0","resultStr":"{\"title\":\"NUMB dysfunction defines a novel mechanism underlying hyperuricemia and gout.\",\"authors\":\"Jingwei Chi, Ying Chen, Changgui Li, Shiguo Liu, Kui Che, Zili Kong, Ziheng Guo, Yanchen Chu, Yajing Huang, Libo Yang, Cunwei Sun, Yunyang Wang, Wenshan Lv, Qing Zhang, Hui Guo, Han Zhao, Zhitao Yang, Lili Xu, Ping Wang, Bingzi Dong, Jianxia Hu, Shihai Liu, Fei Wang, Yanyun Zhao, Mengmeng Qi, Yu Xin, Huiqi Nan, Xiangzhong Zhao, Wei Zhang, Min Xiao, Ke Si, Yangang Wang, Yihai Cao\",\"doi\":\"10.1038/s41421-024-00708-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMB<sup>R630H</sup>) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMB<sup>R630H</sup> knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMB<sup>R630H</sup> knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.</p>\",\"PeriodicalId\":9674,\"journal\":{\"name\":\"Cell Discovery\",\"volume\":\"10 1\",\"pages\":\"106\"},\"PeriodicalIF\":13.0000,\"publicationDate\":\"2024-10-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494200/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Discovery\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s41421-024-00708-6\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Discovery","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41421-024-00708-6","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

肾脏排泄功能缺陷和尿酸生成增加会导致高尿酸血症,从而诱发痛风。然而,尿酸排泄缺陷的分子机制在很大程度上仍然未知。在此,我们报告了一个遗传性痛风家族中前所未有的 NUMB 基因罕见遗传变异,该变异是通过无偏见的全基因组测序方法确定的。这种位于 NUMB 基因保守区的功能失调错义变体(NUMBR630H)通过自噬依赖机制在细胞内重新分布和降解。从机理上讲,我们发现尿酸转运体 ATP 结合盒 G 亚家族成员 2(ABCG2)通过其细胞内 YxNxxF 基序成为一种新型 NUMB 结合蛋白。在极化的肾小管上皮细胞(RTECs)中,NUMB促进了ABCG2向顶端质膜的迁移。遗传性 NUMB 功能缺失导致 ABCG2 在基底侧域重新分布,最终导致尿酸排泄缺陷。为了再现人类痛风患者的临床症状,我们培育了一个 NUMBR630H 基因敲入小鼠品系,结果显示血清尿酸盐明显增加,尿酸排泄减少。NUMBR630H 基因敲入小鼠表现出临床相关的高尿酸血症。总之,我们发现了一种新的 NUMB 介导的尿酸排泄机制,并发现了 NUMB 在人类中的功能性错义变体,它会导致高尿酸血症和痛风。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NUMB dysfunction defines a novel mechanism underlying hyperuricemia and gout.

Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMBR630H) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMBR630H knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMBR630H knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信