title: Complexity, contradictions, and conundrums: studying post-proteasomal proteolysis in HLA class I antigen presentation.
abstract: The vast majority of the peptides produced during protein degradation by the cytosolic proteasome-ubiquitin system are consecutively hydrolyzed to single amino acids by multiple cytosolic peptidases preferring intermediate length or short substrates. The small fraction of peptides surviving the aggressive cytosolic environment can be recruited for presentation by major histocompatibility complex (MHC) class I molecules. However, such peptides may frequently have to be adapted to the strict MHC class I-binding requirements by one or several N-terminal-trimming steps. A recent model proposes that an initial step, in which peptides of 15 or more residues are shortened by cytosolic tripeptidylpeptidase II, is followed by additional trimming by cytosolic or endoplasmic reticulum (ER) aminopeptidases. In humans, at least two ER resident aminopeptidases, ERAP1 and ERAP2, contribute to trimming of human leukocyte antigen class I ligands. These interferon-gamma-regulated metallopeptidases show distinct substrate preferences and may have to act in a concerted fashion to remove some complex or longer N-terminal extensions and to trim the full spectrum of precursor peptides. This task is likely facilitated by the formation of presumably heterodimeric ERAP1-2 complexes. RNA interference experiments suggest that both enzymes are important for normal antigen presentation, but precise determination of the extent and the cellular context of their requirement will be left to future experimentation.
authors.affiliation: INSERM U580, Université René Descartes Paris 5, Paris, France.
authors.forename: Loredana
authors.initials: L
authors.lastname: Saveanu
authors.forename: Oliver
authors.initials: O
authors.lastname: Carroll
authors.forename: Yousra
authors.initials: Y
authors.lastname: Hassainya
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
mesh_terms: D000626:Aminopeptidases / Q000276:immunology / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D010450:Endopeptidases / Q000276:immunology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology* / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D010450:Endopeptidases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D046988:Proteasome Endopeptidase Complex