title: Cathepsin G-mediated proteolytic degradation of MHC class I molecules to facilitate immune detection of human glioblastoma cells.
abstract: To mount an adaptive immune response, MHC I molecules present antigenic peptides to CTLs. Transcriptional reduction of MHC I molecules is a strategy of immune evasion, which impairs the detection of infected or tumorous cells by CTLs. Natural killer (NK) cells, on the other hand, eliminate target cells specifically in the absence of MHC I. Consequently, infected or tumorous cells partly retain their MHC I at the cell surface to avoid NK recognition. However, it remains unclear which protease degrades MHC I molecules and how these cells maintain a limited set of MHC I at the cell surface. Here, we demonstrate that cathepsin G (CatG), a serine protease, found in the endocytic compartment of APCs and, to a lesser extent, CatD and CatS proteolytically degrade MHC I molecules. Inhibition of CatG boosted MHC I expression at the cell surface of primary human immune cells. In contrast, human glioblastoma cells do not harbor active CatG and might have lost the ability to proteolytically degrade MHC I during tumorigenesis to avoid NK-mediated killing. Overexpression of CatG in glioblastoma cells resulted in a rapid and efficient MHC I degradation. In conclusion, CatG is an essential protease for regulating MHC I molecules and thus modulation of CatG activity might present a new avenue for therapeutic intervention.
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Palesch
authors.affiliation: Department of Neurosurgery, Ulm University Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Department of Neurosurgery, Ulm University Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Meid
authors.affiliation: Department of Neurosurgery, Ulm University Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Molenda
authors.affiliation: Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Sienczyk
authors.affiliation: Department of Neurosurgery, Ulm University Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Burkhardt
authors.affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Münch
authors.affiliation: Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Prokop
authors.affiliation: Department of Immunology, University of Tübingen, Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanovic
authors.affiliation: Department Pediatrics and Adolescent Medicine, Ulm University Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Mike-Andrew
authors.initials: MA
authors.lastname: Westhoff
authors.affiliation: Department of Neurosurgery, Ulm University Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Marc-Eric
authors.initials: ME
authors.lastname: Halatsch
authors.affiliation: Department of Neurosurgery, Ulm University Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Christian Rainer
authors.initials: CR
authors.lastname: Wirtz
authors.affiliation: Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Zimecki
authors.affiliation: Department of Neurosurgery, Ulm University Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany. timo.burster@uni-ulm.de.|Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland. timo.burster@uni-ulm.de.
authors.forename: Timo
authors.initials: T
authors.lastname: Burster
mesh_terms: D001932:Brain Neoplasms / Q000276:immunology*; D056649:Cathepsin G / Q000502:physiology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D059748:Proteolysis
chemical_list: D015395:Histocompatibility Antigens Class I; D056649:Cathepsin G
keywords: Cathepsin; Glioblastoma; Immune evasion; MHC I
references.citation: Nat Med. 1996 Mar;2(3):338-42
references.pmid: 8612235
references.citation: Nat Rev Immunol. 2011 Nov 11;11(12):823-36
references.pmid: 22076556
references.citation: Int Rev Immunol. 2001 Jun;20(3-4):333-70
references.pmid: 11878509
references.citation: PLoS One. 2014 Oct 30;9(10):e111819
references.pmid: 25356585
references.citation: J Virol. 2004 Feb;78(3):1109-20
references.pmid: 14722266
references.citation: Cancer Immunol Immunother. 2012 Jan;61(1):119-25
references.pmid: 22116347
references.citation: J Neurosurg. 1997 Mar;86(3):525-31
references.pmid: 9046311
references.citation: Anal Biochem. 2012 Feb 15;421(2):667-72
references.pmid: 22178917
references.citation: Nat Immunol. 2008 May;9(5):477-80
references.pmid: 18425103
references.citation: Acta Biochim Pol. 2011;58(1):39-44
references.pmid: 21383996
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3491-6
references.pmid: 18305173
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3429-33
references.pmid: 1565634
references.citation: Mol Immunol. 2009 Sep;46(15):2994-9
references.pmid: 19615749
references.citation: Chem Biol. 2000 Aug;7(8):569-81
references.pmid: 11048948
references.citation: Cell Host Microbe. 2009 Nov 19;6(5):409-21
references.pmid: 19917496
references.citation: Eur J Immunol. 1995 Apr;25(4):1063-70
references.pmid: 7537671
references.citation: Nature. 1990 Aug 16;346(6285):655-7
references.pmid: 2166918
references.citation: Int J Cancer. 2015 Feb 15;136(4):E173-87
references.pmid: 25123598
references.citation: Genes Dev. 2001 Jun 1;15(11):1311-33
references.pmid: 11390353
references.citation: Lab Invest. 2005 Mar;85(3):328-41
references.pmid: 15716863
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10326-31
references.pmid: 10468607
references.citation: Nature. 2006 Nov 2;444(7115):115-8
references.pmid: 17051151
references.citation: J Immunol. 1991 Mar 15;146(6):1862-7
references.pmid: 2005381
references.citation: Immunology. 2010 Jul;130(3):436-46
references.pmid: 20331476