Both IRAK3 and IRAK1 Activate the MyD88-TRAF6 Pathway in Zebrafish.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Panwei Weng, Mengjiao Lan, Hao Zhang, Huiping Fan, Xiao Wang, Chenrui Ran, Zirui Yue, Jiaxuan Hu, Anlong Xu, Shengfeng Huang
{"title":"Both IRAK3 and IRAK1 Activate the MyD88-TRAF6 Pathway in Zebrafish.","authors":"Panwei Weng, Mengjiao Lan, Hao Zhang, Huiping Fan, Xiao Wang, Chenrui Ran, Zirui Yue, Jiaxuan Hu, Anlong Xu, Shengfeng Huang","doi":"10.4049/jimmunol.2400054","DOIUrl":null,"url":null,"abstract":"<p><p>IL-1R-associated kinases (IRAKs) are signal transducers of the TLR/IL-1R-MyD88-TRAF6 pathways. Vertebrates possess two IRAK lineages, IRAK1/2/3 and IRAK4. In mammals, IRAK4/IRAK1 and IRAK4/IRAK2 are pathway enhancers, whereas IRAK3 is a repressor. However, in bony fish, IRAK2 is absent, and it remains elusive how fish IRAK1/3/4 functionally differ from their mammalian counterparts. In this study, we explored this using the zebrafish model. First, we showed that in human 293T cells, zebrafish IRAK1 and IRAK4 were components of the Myddosome (MyD88-IRAK4-IRAK1) complex, with IRAK1 serving as a potent pathway enhancer. Then, we discovered two zebrafish IRAK3 variants: one (IRAK3a) contains an N-terminal Death domain, a middle pseudokinase domain, and a C-terminal TRAF6-binding domain, whereas the other (IRAK3b) lost both the kinase and TRAF6-binding domains. This truncation of IRAK3 variants could be a conserved phenomenon in fish, because it is also observed in trout and grass carp. We proceeded to show that zebrafish IRAK3a acts as a pathway enhancer by binding with MyD88 and TRAF6, but its activity is milder than IRAK1, possibly because it has no kinase activity. Zebrafish IRAK3b, however, plays a sheer negative role, apparently because of its lack of kinase and TRAF6-binding domains. Moreover, zebrafish IRAK3a/3b inhibit the activity of IRAK1/4, not by interacting with IRAK1/4 but possibly by competing for MyD88 and TRAF6. Finally, we have verified the essential activities of zebrafish IRAK1/3a/3b/4 in zebrafish cells and embryos. In summary, to our knowledge, our findings provide new insights into the molecular functions of fish IRAKs and the evolution of the IRAK functional modes in vertebrates.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4049/jimmunol.2400054","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

IL-1R-associated kinases (IRAKs) are signal transducers of the TLR/IL-1R-MyD88-TRAF6 pathways. Vertebrates possess two IRAK lineages, IRAK1/2/3 and IRAK4. In mammals, IRAK4/IRAK1 and IRAK4/IRAK2 are pathway enhancers, whereas IRAK3 is a repressor. However, in bony fish, IRAK2 is absent, and it remains elusive how fish IRAK1/3/4 functionally differ from their mammalian counterparts. In this study, we explored this using the zebrafish model. First, we showed that in human 293T cells, zebrafish IRAK1 and IRAK4 were components of the Myddosome (MyD88-IRAK4-IRAK1) complex, with IRAK1 serving as a potent pathway enhancer. Then, we discovered two zebrafish IRAK3 variants: one (IRAK3a) contains an N-terminal Death domain, a middle pseudokinase domain, and a C-terminal TRAF6-binding domain, whereas the other (IRAK3b) lost both the kinase and TRAF6-binding domains. This truncation of IRAK3 variants could be a conserved phenomenon in fish, because it is also observed in trout and grass carp. We proceeded to show that zebrafish IRAK3a acts as a pathway enhancer by binding with MyD88 and TRAF6, but its activity is milder than IRAK1, possibly because it has no kinase activity. Zebrafish IRAK3b, however, plays a sheer negative role, apparently because of its lack of kinase and TRAF6-binding domains. Moreover, zebrafish IRAK3a/3b inhibit the activity of IRAK1/4, not by interacting with IRAK1/4 but possibly by competing for MyD88 and TRAF6. Finally, we have verified the essential activities of zebrafish IRAK1/3a/3b/4 in zebrafish cells and embryos. In summary, to our knowledge, our findings provide new insights into the molecular functions of fish IRAKs and the evolution of the IRAK functional modes in vertebrates.

IRAK3 和 IRAK1 都能激活斑马鱼的 MyD88-TRAF6 通路
IL-1R相关激酶(IRAK)是TLR/IL-1R-MyD88-TRAF6通路的信号转导子。脊椎动物有两个 IRAK 家族,即 IRAK1/2/3 和 IRAK4。在哺乳动物中,IRAK4/IRAK1 和 IRAK4/IRAK2 是通路增强因子,而 IRAK3 是抑制因子。然而,在多骨鱼中没有IRAK2,鱼类的IRAK1/3/4与哺乳动物的IRAK1/3/4在功能上有何不同仍是个谜。在本研究中,我们利用斑马鱼模型探讨了这一问题。首先,我们发现在人类 293T 细胞中,斑马鱼 IRAK1 和 IRAK4 是 Myddosome(MyD88-IRAK4-IRAK1)复合体的组成成分,其中 IRAK1 是一种有效的通路增强因子。随后,我们发现了两种斑马鱼 IRAK3 变体:一种(IRAK3a)包含一个 N 端死亡结构域、一个中间假激酶结构域和一个 C 端 TRAF6 结合结构域,而另一种(IRAK3b)则失去了激酶结构域和 TRAF6 结合结构域。IRAK3变体的这种截短可能是鱼类的一种保守现象,因为在鳟鱼和草鱼中也观察到这种现象。我们继续研究发现,斑马鱼IRAK3a通过与MyD88和TRAF6结合起到了通路增强子的作用,但其活性比IRAK1要弱,这可能是因为它没有激酶活性。然而,斑马鱼 IRAK3b 显然由于缺乏激酶和 TRAF6 结合结构域而发挥了纯粹的负面作用。此外,斑马鱼 IRAK3a/3b 不是通过与 IRAK1/4 相互作用,而是可能通过竞争 MyD88 和 TRAF6 来抑制 IRAK1/4 的活性。最后,我们在斑马鱼细胞和胚胎中验证了斑马鱼 IRAK1/3a/3b/4 的基本活性。总之,据我们所知,我们的发现为鱼类 IRAKs 的分子功能以及脊椎动物 IRAK 功能模式的进化提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
×
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