MLN4924 Inhibits Defective Ribosomal Product Antigen Presentation Independently of Direct NEDDylation of Protein Antigens.
MLN4924 Inhibits Defective Ribosomal Product Antigen Presentation Independently of Direct NEDDylation of Protein Antigens.
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MLN 4924抑制缺陷核糖体产物抗原呈递，不依赖于蛋白抗原的直接NEDD化。
DOI：
10.4049/jimmunol.2100584
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发表时间：
2022-05-15
影响因子：
4.4
通讯作者：
Dolan, Brian P.
中科院分区：
文献类型：
--
作者：
Vijayasimha, Kartikeya;Leestemaker-Palmer, Amy L.;Gibbs, James S.;Yewdell, Jonathan W.;Dolan, Brian P.
成功的直接递呈MHC I类抗原依赖于细胞的蛋白质降解机制，以产生抗原肽，这些抗原肽可以装载到MHC I类分子上，由免疫系统的CD8+ T细胞监视。大多数情况下，这一过程涉及泛素-蛋白酶体系统，然而其他泛素样（UBL）蛋白也与蛋白质降解和直接抗原递呈有关。在这里，我们研究了神经元前体细胞表达的发育下调蛋白8 （NEDD8）在小鼠细胞中直接抗原呈递中的作用。NEDD8是与泛素相似性最高的UBL， NEDD8与靶蛋白氨基端融合可导致靶蛋白降解。我们发现，将NEDD8附加到模型抗原卵清蛋白的n端会导致蛋白酶体和自噬蛋白降解途径的降解，但只有蛋白酶体降解，包括蛋白酶体亚基NEDD8最终破坏因子1 (NUB1)，导致肽呈递。当与泛素直接比较时，nedd8融合产生肽的效率较低。然而，用MLN4924处理细胞，使nedd8的连接机制失活，抑制了模型抗原的缺陷核糖体产物（DRiP）衍生形式的肽的呈递。这些结果表明，细胞内的NEDD8活性对直接抗原呈递很重要，而不是直接靶向蛋白质降解。
Successful direct MHC class I antigen presentation is dependent on the protein degradation machinery of the cell to generate antigenic peptides which can be loaded onto MHC class I molecules for surveillance by CD8+ T cells of the immune system. Most often this process involves the ubiquitin-proteasome system, however other ubiquitin-like (UBL) proteins have also been implicated in protein degradation and direct antigen presentation. Here, we examine the role of neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) in direct antigen presentation in mouse cells. NEDD8 is the UBL with highest similarity to ubiquitin and fusion of NEDD8 to the amino-terminus of a target protein can lead to the target proteins degradation. We find that appending NEDD8 to the N-terminus of the model antigen ovalbumin resulted in degradation by both the proteasome and autophagy protein degradation pathways, but only proteasomal degradation, involving the proteasomal subunit NEDD8 ultimate buster 1 (NUB1), resulted in peptide presentation. When directly compared to ubiquitin, NEDD8-fusion was less efficient at generating peptides. However, inactivation of the NEDD8-conugation machinery by treating cells with MLN4924, inhibited the presentation of peptides from the Defective Ribosomal Products (DRiP)-derived form of a model antigen. These results demonstrate that NEDD8 activity in the cell is important for direct antigen presentation, but not by directly targeting proteins for degradation.
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去泛素酶USP14的抑制减少了直接的MHC I类抗原表现。
DOI：
10.4049/jimmunol.1700273
发表时间：
2018-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Palmer AL;de Jong A;Leestemaker Y;Geurink PP;Wijdeven RH;Ovaa H;Dolan BP
通讯作者：
Dolan BP
影响因子：
3.7
作者：
Øynebråten I
通讯作者：
Øynebråten I
影响因子：
3.7
作者：
Palmer AL;Dolan BP
通讯作者：
Dolan BP
DOI：
10.1073/pnas.1112387109
发表时间：
2012-05-01
影响因子：
11.1
作者：
Dolan, Brian P.;Sharma, Aditi A.;Yewdell, Jonathan W.
通讯作者：
Yewdell, Jonathan W.
DOI：
10.1073/pnas.1608644113
发表时间：
2016-08-09
影响因子：
11.1
作者：
Braten, Ori;Livneh, Ido;Ciechanover, Aaron
通讯作者：
Ciechanover, Aaron