Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Amgen Research, Thousand Oaks, CA 91320, USA.
Sci Adv. 2023 Jun 23;9(25):eade7890. doi: 10.1126/sciadv.ade7890.
Peptides from degradation of intracellular proteins are continuously displayed by major histocompatibility complex (MHC) class I. To better understand origins of these peptides, we performed a comprehensive census of the class I peptide repertoire in the presence and absence of ubiquitin-proteasome system (UPS) activity upon developing optimized methodology to enrich for and quantify these peptides. Whereas most class I peptides are dependent on the UPS for their generation, a surprising 30%, enriched in peptides of mitochondrial origin, appears independent of the UPS. A further ~10% of peptides were found to be dependent on the proteasome but independent of ubiquitination for their generation. Notably, clinically achievable partial inhibition of the proteasome resulted in display of atypical peptides. Our results suggest that generation of MHC class I•peptide complexes is more complex than previously recognized, with UPS-dependent and UPS-independent components; paradoxically, alternative protein degradation pathways also generate class I peptides when canonical pathways are impaired.
细胞内蛋白质降解产生的肽段由主要组织相容性复合体 (MHC) Ⅰ类持续呈递。为了更好地了解这些肽段的来源，我们在存在和不存在泛素-蛋白酶体系统 (UPS) 活性的情况下，针对 MHC Ⅰ类肽库进行了全面普查，开发了优化的方法来富集和定量这些肽段。虽然大多数 MHC Ⅰ类肽段的生成依赖于 UPS，但令人惊讶的是，30%（富含线粒体来源的肽段）似乎不依赖 UPS。另外约 10%的肽段的生成依赖于蛋白酶体，但不依赖泛素化。值得注意的是，临床上可实现的蛋白酶体部分抑制导致非典型肽段的呈现。我们的结果表明，MHC Ⅰ类•肽复合物的生成比以前认为的更为复杂，包括 UPS 依赖性和 UPS 非依赖性成分；矛盾的是，当经典途径受损时，替代的蛋白质降解途径也会生成 MHC Ⅰ类肽段。
