Department of Clinical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
J Immunol. 2013 Oct 15;191(8):4020-8. doi: 10.4049/jimmunol.1301496. Epub 2013 Sep 18.
The signal peptide peptidase (SPP) is an intramembrane cleaving aspartyl protease involved in release of leader peptide remnants from the endoplasmic reticulum membrane, hence its name. We now found a new activity of SPP that mediates liberation of C-terminal peptides. In our search for novel proteolytic enzymes involved in MHC class I (MHC-I) presentation, we found that SPP generates the C-terminal peptide-epitope of a ceramide synthase. The display of this immunogenic peptide-MHC-I complex at the cell surface was independent of conventional processing components like proteasome and peptide transporter TAP. Absence of TAP activity even increased the MHC-I presentation of this Ag. Mutagenesis studies revealed the crucial role of the C-terminal location of the epitope and "helix-breaking" residues in the transmembrane region just upstream of the peptide, indicating that SPP directly liberated the minimal 9-mer peptide. Moreover, silencing of SPP and its family member SPPL2a led to a general reduction of surface peptide-MHC-I complexes, underlining the involvement of these enzymes in Ag processing and presentation.
信号肽肽酶（SPP）是一种跨膜天冬氨酸蛋白酶，参与从内质网膜释放前导肽残基，因此得其名。我们现在发现了 SPP 的一种新活性，它介导 C 末端肽的释放。在寻找参与 MHC I（MHC-I）呈递的新型蛋白水解酶的过程中，我们发现 SPP 产生了神经酰胺合酶的 C 末端肽表位。该免疫原性肽-MHC-I 复合物在细胞表面的显示不依赖于蛋白酶体和肽转运体 TAP 等常规加工成分。TAP 活性的缺失甚至增加了该 Ag 的 MHC-I 呈递。突变研究表明，表位的 C 末端位置和跨膜区中紧邻肽的“破环”残基的关键作用，表明 SPP 直接释放最小的 9 肽。此外，SPP 和其家族成员 SPPL2a 的沉默导致表面肽-MHC-I 复合物的普遍减少，强调了这些酶在 Ag 加工和呈递中的参与。
