Destructive potential of the aspartyl protease cathepsin D in MHC class II-restricted antigen processing
Destructive potential of the aspartyl protease cathepsin D in MHC class II-restricted antigen processing
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DOI：
10.1002/eji.200535320
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发表时间：
2005-12-01
影响因子：
5.4
通讯作者：
Watts, C
中科院分区：
文献类型：
--
作者：
Moss, CX;Villadangos, JA;Watts, C
特异性蛋白酶是否影响MHCII类抗原呈递仍不清楚。组织蛋白酶D是最丰富的溶酶体蛋白酶之一，被认为是MHC II类抗原呈递的载体，然而抗原底物与来自抗原呈递细胞的内体/溶酶体的体外消化有时揭示胃蛋白酶抑制剂敏感的乙酰基蛋白酶的主导作用，其中组织蛋白酶D是主要代表。我们测试了肌红蛋白的乙酰化蛋白酶底物是否需要组织蛋白酶D的活性来呈递给T细胞。令人惊讶的是，在缺乏组织蛋白酶D的树突状细胞（DC）中，两种不同的肌红蛋白T细胞表位的呈递被增强而不是被阻碍。这一矛盾通过以下发现得到解决：胃蛋白酶抑制剂敏感的肌红蛋白加工活性持续存在于来自组织蛋白酶D无效DC的溶酶体中，并且这种降低的活性（最可能是由于组织蛋白酶E）更接近肌红蛋白抗原呈递所需的最佳水平。我们的研究结果表明，冗余之间的溶酶体乙酰蛋白酶，并表明，虽然加工活动可以生产的MHC II类T细胞表位生成在一个水平上，他们可以成为破坏性的最佳水平以上。
Whether specific proteases influence MHC class II antigen presentation is still not clearly defined. Cathepsin D, one of the most abundant lysosomal proteases, is thought to be dispensable for MHC class II antigen presentation, yet in vitro digestions of antigen substrates with endosomes/lysosomes from antigen-presenting cells sometimes reveal a dominant role for pepstatin-sensitive aspartyl proteases of which cathepsin D is the major representative. We tested whether the aspartyl protease substrate myoglobin requires cathepsin D activity for presentation to T cells. Surprisingly, in dendritic cells (DC) lacking cathepsin D, presentation of two different myoglobin T cell epitopes was enhanced rather than hindered. This paradox is resolved by the finding that pepstatin-sensitive myoglobin processing activity persists in lysosomes from cathepsin D-null DC and that this reduced activity, most likely due to cathepsin E, is closer to the optimum level required for myoglobin antigen presentation. Our results indicate redundancy among lysosomal aspartyl proteases and show that while processing activities can be productive for MHC class II T cell epitope generation at one level, they can become destructive above an optimal level.