Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation
Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation
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DOI：
10.4049/jimmunol.1103592
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发表时间：
2012-08-15
影响因子：
4.4
通讯作者：
Groettrup, Marcus
中科院分区：
文献类型：
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作者：
Basler, Michael;Lauer, Christoph;Groettrup, Marcus
蛋白酶体负责产生MHC I类分子上呈递的大多数表位。用IFN-γ处理细胞导致组成型催化亚基β 1、β 2和β 5分别被诱导型亚基低分子量多肽（LMP）2（β 1 i）、多催化性内肽酶复合物样-1（β 2 i）和LMP 7（β 5i）取代。这些亚基的掺入是产生许多MHC I类限制性T细胞表位所必需的。免疫蛋白酶体亚基的结构特征而不是蛋白水解活性是产生某些表位所必需的，但其潜在的机制仍然难以捉摸。用LMP 2缺陷型脾细胞进行的实验显示，雄性HY衍生的CTL表位UTY 246 -254的产生依赖于LMP 2。用LMP 2选择性抑制剂处理雄性脾细胞不会减少UTY 246 -254的呈递，而β 1活性的沉默增加UTY 246 -254的呈递。在体外降解实验表明，半胱天冬酶样活性的b1是负责这个CTL表位的破坏，而它被保存时，LMP 2取代β 1。此外，β 5亚基的抑制挽救了流感基质58-66表位的呈递，从而表明类似的机制可以应用于LMP 7对β 5的交换。两者合计，我们的数据提供了一个理由，为什么免疫蛋白酶体亚基的结构特性，而不是它的活性是必需的CTL表位的产生。免疫学杂志，2012，189：1868-1877。
The proteasome is responsible for the generation of most epitopes presented on MHC class I molecules. Treatment of cells with IFN-gamma leads to the replacement of the constitutive catalytic subunits beta 1, beta 2, and beta 5 by the inducible subunits low molecular mass polypeptide (LMP) 2 (beta 1i), multicatalytic endopeptidase complex-like-1 (beta 2i), and LMP7 (beta 5i), respectively. The incorporation of these subunits is required for the production of numerous MHC class I-restricted T cell epitopes. The structural features rather than the proteolytic activity of an immunoproteasome subunit are needed for the generation of some epitopes, but the underlying mechanisms have remained elusive. Experiments with LMP2-deficient splenocytes revealed that the generation of the male HY-derived CTL-epitope UTY246-254 was dependent on LMP2. Treatment of male splenocytes with an LMP2-selective inhibitor did not reduce UTY246-254 presentation, whereas silencing of beta 1 activity increased presentation of UTY246-254. In vitro degradation experiments showed that the caspase-like activity of b1 was responsible for the destruction of this CTL epitope, whereas it was preserved when LMP2 replaced beta 1. Moreover, inhibition of the beta 5 subunit rescued the presentation of the influenza matrix 58-66 epitope, thus suggesting that a similar mechanism can apply to the exchange of beta 5 by LMP7. Taken together, our data provide a rationale why the structural property of an immunoproteasome subunit rather than its activity is required for the generation of a CTL epitope. The Journal of Immunology, 2012, 189: 1868-1877.