Quantitative measurement of the requirement of diverse protein degradation pathways in MHC class I peptide presentation.

Autor: Mamrosh JL; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.; Amgen Research, Thousand Oaks, CA 91320, USA., Sherman DJ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.; Amgen Research, Thousand Oaks, CA 91320, USA., Cohen JR; Process Development, Amgen Inc., Thousand Oaks, CA 91320, USA., Johnston JA; Amgen Research, Thousand Oaks, CA 91320, USA., Joubert MK; Process Development, Amgen Inc., Thousand Oaks, CA 91320, USA., Li J; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.; Amgen Research, Thousand Oaks, CA 91320, USA., Lipford JR; Amgen Research, Thousand Oaks, CA 91320, USA., Lomenick B; Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA., Moradian A; Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA., Prabhu S; Process Development, Amgen Inc., Thousand Oaks, CA 91320, USA., Sweredoski MJ; Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA., Vander Lugt B; Amgen Research, South San Francisco, CA 94080, USA., Verma R; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.; Amgen Research, Thousand Oaks, CA 91320, USA., Deshaies RJ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.; Amgen Research, Thousand Oaks, CA 91320, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 Jun 23; Vol. 9 (25), pp. eade7890. Date of Electronic Publication: 2023 Jun 23.
DOI: 10.1126/sciadv.ade7890
Abstrakt: 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.
Databáze: MEDLINE
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