Roles of p97/VCP in linear ubiquitin mediated NF-kappaB activation

p97/VCP 在线性泛素介导的 NF-κB 激活中的作用

• 批准号: 24790279
• 负责人: NAKAGAWA Tomoko
• 金额: $ 2.83万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24790279/
• 关键词: PUBドメイン; LUBAC; 直鎖状ポリユビキチン鎖; NF-kappaB

The LUBAC ubiquiin ligase is composed of three subunits, HOIP, HOIL-1L and SHARPIN. LUBAC possesses multiple domains, but the role of the PUB domain that exists in the N-terminal region of HOIP had not been addressed. The PUB domain has been identified as a binding domain of p97/VCP. Since p97/VCP has shown to regulate NF-kappaB activation negatively, we examined the role of the PUB domain in LUBAC mediated NF-kappaB activation. To our surprise, in cells expressing a HOIP mutant, which cannot bind p97/VCP, both NF-kappaB activation and linear polyubiquitination of NEMO mediated by TNF-alpha were augmented. We then sought proteins bound to the PUB domain of HOIP and found that two deubiquitinases, OTULIN and CYLD, that specifically cleaved linear chains as interacting proteins of HOIP PUB. Both OTULIN and CYLD bind to the PUB domain of HOIP directly and down-regulated LUBAC-mediated NF-kappaB activation.

LUBAC泛素连接酶由三个亚基HOIP、HOIL-1L和SHARPIN组成。LUBAC具有多个域，但存在于HOIP n端区域的PUB域的作用尚未得到解决。PUB结构域被确定为p97/VCP的一个结合结构域。由于p97/VCP已显示出负向调节NF-kappaB激活，我们研究了PUB结构域在LUBAC介导的NF-kappaB激活中的作用。令我们惊讶的是，在表达不能结合p97/VCP的HOIP突变体的细胞中，NF-kappaB激活和tnf - α介导的NEMO线性多泛素化都增强了。然后，我们寻找与HOIP的PUB结构域结合的蛋白质，并发现两种去泛素酶OTULIN和CYLD作为HOIP PUB的相互作用蛋白特异性地切割线性链。OTULIN和CYLD都直接结合到HOIP的PUB结构域，并下调lubac介导的NF-kappaB激活。

项目成果

京都大学・大学院医学研究科・細胞機能制御学

京都大学医学研究科细胞功能调节学科

Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN

• DOI: 10.1111/gtc.12128
• 发表时间: 2014-03-01
• 期刊: GENES TO CELLS
• 影响因子: 2.1
• 作者: Takiuchi, Tsuyoshi;Nakagawa, Tomoko;Iwai, Kazuhiro
• 通讯作者: Iwai, Kazuhiro