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Role for Ribosome-Associated Quality Control in Sampling Proteins for MHC Class I-Mediated Antigen Presentation

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Role for Ribosome-Associated Quality Control in Sampling Proteins for MHC Class I-Mediated Antigen Presentation Role for ribosome-associated quality control in sampling proteins for MHC class I-mediated antigen presentation Débora Broch Trentinia, Matteo Pecorarob, Shivani Tiwaryc, Jürgen Coxc,d, Matthias Mannb, Mark S. Hippa,1,2, and F. Ulrich Hartla,2 aDepartment of Cellular Biochemistry, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; bDepartment of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; cComputational Systems Biochemistry Research Group, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany; and dDepartment of Biological and Medical Psychology, University of Bergen, 5009 Bergen, Norway Edited by Alexander Varshavsky, California Institute of Technology, Pasadena, CA, and approved January 20, 2020 (received for review August 21, 2019) Mammalian cells present a fingerprint of their proteome to the that production of an antigenic peptide would depend largely on adaptive immune system through the display of endogenous peptides the rate of translation of the corresponding protein, and less on its on MHC-I complexes. MHC-I−bound peptides originate from protein relative abundance or turnover once folded and assembled. This degradation by the proteasome, suggesting that stably folded, long- would be particularly important for viral proteins, which constitute lived proteins could evade monitoring. Here, we investigate the role only a minute fraction of the total cellular pool of proteins at the in antigen presentation of the ribosome-associated quality control early stages of infection (7). A number of studies showed that (RQC) pathway for the degradation of nascent polypeptides that are presentation of certain model proteins is inefficient in the absence encoded by defective messenger RNAs and undergo stalling at the of active synthesis, despite the presence of a large pool of mature ribosome during translation. We find that degradation of model pro- forms being degraded (16–18), while others reported productive teins by RQC results in efficient MHC-I presentation, independent presentation of mature proteins (19, 20). The mechanism of DRiP of their intrinsic folding properties. Quantitative profiling of MHC-I generation and the overall contribution of DRiPs to antigen peptides in wild-type and RQC-deficient cells by mass spectrometry presentation remain areas of active research. showed that RQC substantially contributes to the composition of the Here, we test the hypothesis that the ribosome-associated BIOCHEMISTRY immunopeptidome. Our results also identify endogenous substrates quality control (RQC) machinery may play a role in MHC-I of the RQC pathway in human cells and provide insight into common antigen presentation. RQC is a conserved eukaryotic pathway principles causing ribosome stalling under physiological conditions. ribosome-associated quality control | Listerin | MHC-I | immunopeptidome Significance Pathogens and tumors are detected by the immune system through he major histocompatibility complex (MHC) molecules play the display of intracellular peptides on MHC-I complexes. These a central role in the vertebrate adaptive immune system. T peptides are generated by the ubiquitin−proteasome system pref- MHC class I binds to short peptides (8 to 11 amino acids long) erentially from newly synthesized polypeptides. Here we show that sampled from the proteolytic products of intracellular proteins. the ribosome-associated quality control (RQC) pathway, responsible MHC-I−loaded peptides are presented at the cell surface, where for proteasomal degradation of polypeptide chains that stall during they are surveyed by CD8+ T cells for the presence of non−self- translation, mediates efficient antigen presentation of model pro- peptides (1). This system, present in all nucleated cells of higher teins independent of their intrinsic folding properties. Immuno- vertebrates, enables the recognition of cells infected with viruses peptidome characterization of RQC-deficient cells shows that RQC and other intracellular parasites, or cells accumulating aberrant contributes to the presentation of a wide variety of proteins, in- proteins resulting from malignant transformation. The presented cluding proteins that may otherwise evade presentation due to peptides originate mostly from degradation by the ubiquitin− efficient folding. By identifying endogenous substrates of the RQC proteasome system (2, 3), which is responsible for the controlled pathway in human cells, our results also enable the analysis of turnover of the great majority of cellular proteins, and for the common principles causing ribosome stalling under physiological rapid degradation of defective species (4). The immune response conditions. is remarkably efficient. In cultured cells, CD8+ T cells can rec- ognize infected cells in less than 60 min after viral penetration Author contributions: D.B.T., M.M., M.S.H., and F.U.H. designed research; D.B.T., M.P., and (5), despite the fact that viral proteins are usually very stable and S.T. performed research; D.B.T., M.P., S.T., J.C., M.M., M.S.H., and F.U.H. analyzed data; have slow turnover rates (6). Accordingly, cells require a mech- and D.B.T., M.S.H., and F.U.H. wrote the paper. anism for rapidly generating peptides from long-lived viral pro- The authors declare no competing interest. teins synthesized upon infection. This article is a PNAS Direct Submission. To explain the kinetic discrepancy between protein half-life This open access article is distributed under Creative Commons Attribution-NonCommercial- and MHC-I presentation, defective ribosomal products (DRiPs) NoDerivatives License 4.0 (CC BY-NC-ND). have been proposed to act as a significant source of self-peptides Data deposition: The mass spectrometry proteomics data have been deposited to the and viral peptides. DRiPs were defined as proteins that do not ProteomeXchange Consortium via the PRIDE partner repository with the dataset reach mature (stable) conformation and, unable to fold or as- identifier PXD014644. semble correctly, are targeted for rapid proteasomal degradation 1Present addresses: Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (7). The DRiP designation later evolved to include errors in and School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, transcription, splicing, and translation (8). While estimates for the 26111 Oldenburg, Germany. fraction of rapidly degraded newly synthesized proteins varied 2To whom correspondence may be addressed. Email: [email protected] or uhartl@ considerably (6, 9–13), it has also been suggested that proteasome biochem.mpg.de. substrates differ in their access to MHC-I presentation, with “true This article contains supporting information online at https://www.pnas.org/lookup/suppl/ DRiPs” undergoing privileged processing for presentation (14, doi:10.1073/pnas.1914401117/-/DCSupplemental. 15). Therefore, one appealing notion of the DRiP hypothesis is First published February 11, 2020. www.pnas.org/cgi/doi/10.1073/pnas.1914401117 PNAS | February 25, 2020 | vol. 117 | no. 8 | 4099–4108 Downloaded by guest on October 1, 2021 that removes nascent polypeptide chains from ribosomes that Experiments were performed using stable monoclonal cell lines for have stalled during translation (21) and thus qualify as DRiPs. In each construct in WT and in RQC-deficient (Listerin-KO) cells contrast to quality control mechanisms that monitor the folding obtained by CRISPR/Cas (SI Appendix,Fig.S1). Cycloheximide state of newly synthesized polypeptides, RQC senses the state of (CHX) chase experiments confirmed that both DD fusions (STOP translation (22). RQC comprises five steps: sensing of elongation versions) were stable in the presence of ligand (half-life of >9h), stalling, ribosome splitting and messenger RNA (mRNA) dis- but rapidly degraded in the absence of ligand, with a half-life of sociation, assembly of the RQC machinery on the 60S subunit, ∼4 h for FKBP STOP and ∼30 min for DHFR STOP (Fig. 1B). ubiquitylation of the nascent chain, and its extraction for pro- Thus the FKBPDD and DHFRDD of the fusion proteins fold teasomal degradation. The core components of the RQC ma- independently of the SIINFEKL-eGFP and are stabilized by the chinery in mammals are the ubiquitin ligase Listerin (23) and the respective ligand. factors NEMF and TCF25 (respectively, Ltn1/Rqc2/Rqc1 in Next, we compared the effect of DD ligand and the protea- yeast) (21, 22, 24). NEMF/Rqc2 recognizes the peptidyl−transfer some inhibitor MG132 on protein levels. Addition of ligand for 4 h RNA moiety at the interface of the dissociated 60S ribosome and increased GFP levels approximately fivefold for the STOP pro- recruits Listerin/Ltn1 (24, 25), which mediates ubiquitylation of teins and approximately twofold for the NS proteins (Fig. 1C). the stalled polypeptide near the ribosome exit tunnel (25–27). Combining DD ligand with MG132 did not result in a further RQC is intimately linked to two mRNA degradation pathways stabilization of the STOP proteins, but rather decreased their level that take place in the cytoplasm: nonstop mRNA decay (28) and by ∼20%, as overall protein synthesis slowed after 1 h of protea- no-go decay (29), which recognize mRNAs that lack stop codons some inhibition (38) (Fig. 1C and SI Appendix,Fig.S2). In con- and mRNAs that present obstacles to elongation, respectively. trast, NS protein GFP levels increased ∼18-fold upon combined
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