Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells.
Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells.
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DOI：
10.4049/jimmunol.1101643
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发表时间：
2011-09-15
期刊：
影响因子：
--
通讯作者：
Shin JS
中科院分区：
文献类型：
--
作者：
Baravalle G;Park H;McSweeney M;Ohmura-Hoshino M;Matsuki Y;Ishido S;Shin JS
树突状细胞（dc）需要CD86等共刺激分子来有效激活T细胞以诱导适应性免疫。dc在静止状态下维持最低水平的CD86表达，但在LPS刺激下上调CD86表达水平。lps刺激的树突状细胞产生免疫抑制细胞因子IL-10，其以自分泌方式调节CD86水平。有趣的是，严格控制CD86背后的潜在分子机制尚不完全清楚。在这项研究中，我们报道了CD86在dc中通过MARCH1 E3泛素连接酶泛素化，并且这种泛素化在CD86的调控中起关键作用。赖氨酸267位点的泛素化在这一调控中发挥了最关键的作用。CD86在缺乏march1的dc中泛素化程度远低于野生型dc，这也与CD86表达的显著增加相关。重要的是，在脂多糖激活后，CD86在dc中持续泛素化，这是由于自分泌IL-10抑制了MARCH1下调。因此，缺乏MARCH1的dc和表达泛素化抗性突变CD86的dc都无法调节CD86对自分泌IL-10的响应。表达泛素化抗性突变CD86的树突状细胞在静止状态以及对自分泌IL-10的反应中无法控制其T细胞激活能力。这些研究表明，泛素化是DCs控制CD86表达和调节其ag呈递功能的重要机制。
Dendritic cells (DCs) require costimulatory molecules such as CD86 to efficiently activate T cells for the induction of adaptive immunity. DCs maintain minimal levels of CD86 expression at rest, but upregulate levels upon LPS stimulation. LPS-stimulated DCs produce the immune suppressive cytokine IL-10 that acts in an autocrine manner to regulate CD86 levels. Interestingly, the underlying molecular mechanism behind the tight control of CD86 is not completely understood. In this study, we report that CD86 is ubiquitinated in DCs via MARCH1 E3 ubiquitin ligase and that this ubiquitination plays a key role in CD86 regulation. Ubiquitination at lysine 267 played the most critical role for this regulation. CD86 is ubiquitinated in MARCH1-deficient DCs to a much lesser degree than in wild-type DCs, which also correlated with a significant increase in CD86 expression. Importantly, CD86 is continuously ubiquitinated in DCs following activation by LPS, and this was due to the autocrine IL-10 inhibition of MARCH1 downregulation. Accordingly, DCs lacking MARCH1 and DCs expressing ubiquitination-resistant mutant CD86 both failed to regulate CD86 in response to autocrine IL-10. DCs expressing ubiquitination-resistant mutant CD86 failed to control their T cell-activating abilities at rest as well as in response to autocrine IL-10. These studies suggest that ubiquitination serves as an important mechanism by which DCs control CD86 expression and regulate their Ag-presenting functions.
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DOI：
10.1084/jem.20092203
发表时间：
2011-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Tze LE;Horikawa K;Domaschenz H;Howard DR;Roots CM;Rigby RJ;Way DA;Ohmura-Hoshino M;Ishido S;Andoniou CE;Degli-Esposti MA;Goodnow CC
通讯作者：
Goodnow CC
影响因子：
5.4
作者：
Bartee, E;Mansouri, M;Früh, K
通讯作者：
Früh, K
DOI：
10.1073/pnas.0708874105
发表时间：
2008-03-04
影响因子：
11.1
作者：
De Gassart, Aude;Camosseto, Voahirana;Gatti, Evelina
通讯作者：
Gatti, Evelina
影响因子：
15.9
作者：
Coscoy, L;Ganem, D
通讯作者：
Ganem, D
影响因子：
82.9
作者：
Brooks, David G.;Trifilo, Matthew J.;Oldstone, Michael B. A.
通讯作者：
Oldstone, Michael B. A.