title: Targeted delivery of an antigenic peptide to the endoplasmic reticulum: application for development of a peptide therapy for ankylosing spondylitis.
abstract: The development of suitable methods to deliver peptides specifically to the endoplasmic reticulum (ER) can provide some potential therapeutic applications of such peptides. Ankylosing spondylitis (AS) is strongly associated with the expression of human leukocytic antigen-B27 (HLA-B27). HLA-B27 heavy chain (HC) has a propensity to fold slowly resulting in the accumulation of misfolded HLA-B27 HC in the ER, triggering the unfolded protein response, and forming a homodimer, (B27-HC)2. Natural killer cells and T-helper 17 cells are then activated, contributing to the major pathogenic potentials of AS. The HLA-B27 HC is thus an important target, and delivery of an HLA-B27-binding peptide to the ER capable of promoting HLA-B27 HC folding is a potential mechanism for AS therapy. Here, we demonstrate that a His6-ubiquitin-tagged Tat-derived peptide (THU) can deliver an HLA-B27-binding peptide to the ER promoting HLA-B27 HC folding. The THU-HLA-B27-binding peptide fusion protein crossed the cell membrane to the cytosol through the Tat-derived peptide. The HLA-B27-binding peptide was specifically cleaved from THU by cytosolic ubiquitin C-terminal hydrolases and subsequently transported into the ER by the transporter associated with antigen processing. This approach has potential application in the development of peptide therapy for AS.
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan ; Section of Allergy, Immunology, and Rheumatology, Department of Medicine, Buddhist DaLin Tzu-Chi Hospital, Chia-Yi, Taiwan.
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Yu
authors.forename: Ming-Chi
authors.initials: MC
authors.lastname: Lu
authors.forename: Chin
authors.initials: C
authors.lastname: Li
authors.forename: Hsien-Lu
authors.initials: HL
authors.lastname: Huang
authors.forename: Kuang-Yung
authors.initials: KY
authors.lastname: Huang
authors.forename: Su-Qin
authors.initials: SQ
authors.lastname: Liu
authors.forename: Ning-Sheng
authors.initials: NS
authors.lastname: Lai
authors.forename: Hsien-Bin
authors.initials: HB
authors.lastname: Huang
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D016503:Drug Delivery Systems; D004720:Endonucleases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D015796:HLA-B27 Antigen / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000378:metabolism; D013167:Spondylitis, Ankylosing / Q000188:drug therapy*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry*
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D015796:HLA-B27 Antigen; D007143:Immunoglobulin Heavy Chains; D010455:Peptides; D011994:Recombinant Proteins; C073119:TAP1 protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus; D004720:Endonucleases