Ludwig Institute for Cancer Research, Brussels Branch, 1200 Brussels, Belgium.
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18599-604. doi: 10.1073/pnas.1009778107. Epub 2010 Oct 11.
Most antigenic peptides presented by MHC class I molecules result from the degradation of intracellular proteins by the proteasome. In lymphoid tissues and cells exposed to IFNγ, the standard proteasome is replaced by the immunoproteasome, in which all of the standard catalytic subunits β1, β2, and β5 are replaced by their inducible counterparts β1i, β2i, and β5i, which have different cleavage specificities. The immunoproteasome thereby shapes the repertoire of antigenic peptides. The existence of additional forms of proteasomes bearing a mixed assortment of standard and inducible catalytic subunits has been suggested. Using a new set of unique subunit-specific antibodies, we have now isolated, quantified, and characterized human proteasomes that are intermediate between the standard proteasome and the immunoproteasome. They contain only one (β5i) or two (β1i and β5i) of the three inducible catalytic subunits of the immunoproteasome. These intermediate proteasomes represent between one-third and one-half of the proteasome content of human liver, colon, small intestine, and kidney. They are also present in human tumor cells and dendritic cells. We identified two tumor antigens of clinical interest that are processed exclusively either by intermediate proteasomes β5i (MAGE-A3(271-279)) or by intermediate proteasomes β1i-β5i (MAGE-A10(254-262)). The existence of these intermediate proteasomes broadens the repertoire of antigens presented to CD8 T cells and implies that the antigens presented by a given cell depend on their proteasome content.
大多数由 MHC I 类分子呈递的抗原肽来源于蛋白酶体对细胞内蛋白的降解。在 IFNγ 作用下的淋巴组织和细胞中，标准蛋白酶体被免疫蛋白酶体所取代，标准的所有催化亚基β1、β2 和β5 都被它们的诱导型对应物β1i、β2i 和β5i 所取代，后者具有不同的切割特异性。免疫蛋白酶体从而塑造了抗原肽的库。已经有人提出存在具有标准和诱导型催化亚基混合的其他形式的蛋白酶体。使用一组新的独特的亚基特异性抗体，我们现在已经分离、定量和表征了人类蛋白酶体，它们处于标准蛋白酶体和免疫蛋白酶体之间。它们只包含免疫蛋白酶体的三个诱导型催化亚基中的一个（β5i）或两个（β1i 和β5i）。这些中间蛋白酶体代表人类肝脏、结肠、小肠和肾脏中蛋白酶体含量的三分之一到一半。它们也存在于人类肿瘤细胞和树突状细胞中。我们鉴定了两个具有临床意义的肿瘤抗原，它们仅由中间蛋白酶体β5i（MAGE-A3(271-279)）或中间蛋白酶体β1i-β5i（MAGE-A10(254-262)）进行加工。这些中间蛋白酶体拓宽了 CD8 T 细胞呈递的抗原谱，并意味着给定细胞呈递的抗原取决于其蛋白酶体的含量。
