PMID- 30315122 OWN - NLM STAT- MEDLINE DCOM- 20190926 LR - 20190926 IS - 2470-9468 (Electronic) IS - 2470-9468 (Linking) VI - 3 IP - 28 DP - 2018 Oct 12 TI - A subset of HLA-I peptides are not genomically templated: Evidence for cis- and trans-spliced peptide ligands. LID - eaar3947 [pii] LID - 10.1126/sciimmunol.aar3947 [doi] AB - The diversity of peptides displayed by class I human leukocyte antigen (HLA) plays an essential role in T cell immunity. The peptide repertoire is extended by various posttranslational modifications, including proteasomal splicing of peptide fragments from distinct regions of an antigen to form nongenomically templated cis-spliced sequences. Previously, it has been suggested that a fraction of the immunopeptidome constitutes such cis-spliced peptides; however, because of computational limitations, it has not been possible to assess whether trans-spliced peptides (i.e., the fusion of peptide segments from distinct antigens) are also bound and presented by HLA molecules, and if so, in what proportion. Here, we have developed and applied a bioinformatic workflow and demonstrated that trans-spliced peptides are presented by HLA-I, and their abundance challenges current models of proteasomal splicing that predict cis-splicing as the most probable outcome. These trans-spliced peptides display canonical HLA-binding sequence features and are as frequently identified as cis-spliced peptides found bound to a number of different HLA-A and HLA-B allotypes. Structural analysis reveals that the junction between spliced peptides is highly solvent exposed and likely to participate in T cell receptor interactions. These results highlight the unanticipated diversity of the immunopeptidome and have important implications for autoimmunity, vaccine design, and immunotherapy. CI - Copyright (c) 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - Faridi, Pouya AU - Faridi P AUID- ORCID: 0000-0002-2712-3356 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Li, Chen AU - Li C AUID- ORCID: 0000-0002-1847-754X AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - Department of Biology, Institute of Molecular Systems Biology,ETH Zurich, Zurich 8093, Switzerland. FAU - Ramarathinam, Sri H AU - Ramarathinam SH AUID- ORCID: 0000-0002-2787-1282 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Vivian, Julian P AU - Vivian JP AUID- ORCID: 0000-0002-9400-4437 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia. FAU - Illing, Patricia T AU - Illing PT AUID- ORCID: 0000-0002-3870-0796 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Mifsud, Nicole A AU - Mifsud NA AUID- ORCID: 0000-0001-8647-2102 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Ayala, Rochelle AU - Ayala R AUID- ORCID: 0000-0001-8538-8857 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Song, Jiangning AU - Song J AUID- ORCID: 0000-0001-8031-9086 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - Monash Centre for Data Science, Faculty of Information Technology, Monash University, Melbourne, Victoria 3800, Australia. FAU - Gearing, Linden J AU - Gearing LJ AD - Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Department of Molecular and Translational Science, School of Clinical Science, Monash University, Clayton, Victoria 3168, Australia. FAU - Hertzog, Paul J AU - Hertzog PJ AD - Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research and Department of Molecular and Translational Science, School of Clinical Science, Monash University, Clayton, Victoria 3168, Australia. FAU - Ternette, Nicola AU - Ternette N AUID- ORCID: 0000-0002-9283-0743 AD - Jenner Institute, University of Oxford, Oxford OX3 7FZ, UK. FAU - Rossjohn, Jamie AU - Rossjohn J AUID- ORCID: 0000-0002-2020-7522 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia. AD - Institute of Infection and Immunity, Cardiff University School of Medicine,Heath Park, Cardiff CF14 4XN, UK. FAU - Croft, Nathan P AU - Croft NP AUID- ORCID: 0000-0002-2128-5127 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. anthony.purcell@monash.edu nathan.croft@monash.edu. FAU - Purcell, Anthony W AU - Purcell AW AUID- ORCID: 0000-0003-0532-8331 AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. anthony.purcell@monash.edu nathan.croft@monash.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Sci Immunol JT - Science immunology JID - 101688624 RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Ligands) RN - 0 (Peptides) SB - IM CIN - Sci Immunol. 2019 Aug 16;4(38):. PMID: 31420320 CIN - Sci Immunol. 2019 Aug 16;4(38):. PMID: 31420321 MH - Cells, Cultured MH - Histocompatibility Antigens Class I/*chemistry/immunology MH - Humans MH - Ligands MH - Peptides/*chemistry/immunology MH - Protein Conformation MH - Stereoisomerism EDAT- 2018/10/14 06:00 MHDA- 2019/09/27 06:00 CRDT- 2018/10/14 06:00 PHST- 2017/11/02 00:00 [received] PHST- 2018/05/29 00:00 [revised] PHST- 2018/08/31 00:00 [accepted] PHST- 2018/10/14 06:00 [entrez] PHST- 2018/10/14 06:00 [pubmed] PHST- 2019/09/27 06:00 [medline] AID - 3/28/eaar3947 [pii] AID - 10.1126/sciimmunol.aar3947 [doi] PST - ppublish SO - Sci Immunol. 2018 Oct 12;3(28):eaar3947. doi: 10.1126/sciimmunol.aar3947.