Zaiss Dietmar M W, Standera Sybille, Kloetzel Peter-M, Sijts Alice J A M
Institute of Biochemistry, Medical Faculty Charité, Humboldt University, D-10117 Berlin, Germany.
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14344-9. doi: 10.1073/pnas.212257299. Epub 2002 Oct 8.
Regulation of the proteasome system, which is responsible for the generation of most MHC class I-bound peptides, occurs through the interaction of the 20S proteasome with several regulatory proteins. One of these is PI31, which acts in vitro as an inhibitor of proteasome activity. Here, we demonstrate that, rather than inhibiting proteasome function, PI31 acts as a selective modulator of the proteasome-mediated steps in MHC class I antigen processing. Overexpression of PI31 in mouse embryonic cells has no impact on proteasome-mediated proteolysis. Instead, PI31, which localizes at the nuclear envelope/endoplasmic reticulum membrane, selectively interferes with the maturation of immunoproteasome precursor complexes. Consequently, overexpression of PI31 abrogates MHC class I presentation of an immunoproteasome-dependent cytotoxic T lymphocyte epitope and reduces the surface MHC class I levels on IFN-gamma-treated mouse embryonic cells. Thus, PI31 represents a cellular regulator of proteasome formation and of proteasome-mediated antigen processing.
蛋白酶体系统负责生成大多数与MHC I类分子结合的肽段，该系统的调节是通过20S蛋白酶体与几种调节蛋白的相互作用实现的。其中之一是PI31，它在体外作为蛋白酶体活性的抑制剂发挥作用。在此，我们证明，PI31并非抑制蛋白酶体功能，而是作为蛋白酶体介导的MHC I类抗原加工步骤的选择性调节剂。PI31在小鼠胚胎细胞中的过表达对蛋白酶体介导的蛋白水解没有影响。相反，定位于核膜/内质网膜的PI31选择性地干扰免疫蛋白酶体前体复合物的成熟。因此，PI31的过表达消除了免疫蛋白酶体依赖性细胞毒性T淋巴细胞表位的MHC I类呈递，并降低了经γ干扰素处理的小鼠胚胎细胞表面MHC I类分子的水平。因此，PI31代表了蛋白酶体形成和蛋白酶体介导的抗原加工的细胞调节剂。
