title: No major role for insulin-degrading enzyme in antigen presentation by MHC molecules.
abstract: Antigen presentation by MHC class I molecules requires degradation of epitope source proteins in the cytosol. Although the preeminent role of the proteasome is clearly established, evidence suggesting a significant role for proteasome-independent generation of class I ligands has been reported repeatedly. However, an enzyme responsible for such a role has not been identified. Recently insulin-degrading enzyme (IDE) was shown to produce an antigenic peptide derived from the tumor antigen MAGE-A3 in an entirely proteasome-independent manner, raising the question of the global impact of IDE in MHC class I antigen processing. Here we report that IDE knockdown in human cell lines, or knockout in two different mouse strains, has no effect on cell surface expression of various MHC class I molecules, including allomorphs such as HLA-A3 and HLA-B27 suggested to be loaded in an at least a partly proteasome-independent manner. Moreover, reduced or absent IDE expression does not affect presentation of five epitopes including epitopes derived from beta amyloid and proinsulin, two preferred IDE substrates. Thus, IDE does not play a major role in MHC class I antigen processing, confirming the dominant and almost exclusive role of the proteasome in cytosolic production of MHC class I ligands.
authors: Institut National de la Santé et de la Recherche Médicale, Unité 1013, Paris, France ; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.
authors: Slobodan
authors: S
authors: Culina
authors: Institut National de la Santé et de la Recherche Médicale, Unité 1013, Paris, France ; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.
authors: François-Xavier
authors: FX
authors: Mauvais
authors: Institut National de la Santé et de la Recherche Médicale, Unité 1013, Paris, France ; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.
authors: Hsiang-Ting
authors: HT
authors: Hsu
authors: Institut National de la Santé et de la Recherche Médicale, Unité 1013, Paris, France ; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.
authors: Anne
authors: A
authors: Burgevin
authors: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts, United States of America.
authors: Suzanne
authors: S
authors: Guénette
authors: Institut National de la Santé et de la Recherche Médicale, Unité 1013, Paris, France ; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.
authors: Anna
authors: A
authors: Moser
authors: Institut National de la Santé et de la Recherche Médicale, Unité 1013, Paris, France ; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France.
authors: Peter
authors: P
authors: van Endert
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D005805:Genes, MHC Class I / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D007339:Insulysin; D046988:Proteasome Endopeptidase Complex