title: Ubiquitin-independent proteosomal degradation of myelin basic protein contributes to development of neurodegenerative autoimmunity.
abstract: Recent findings indicate that the ubiquitin-proteasome system is involved in the pathogenesis of cancer as well as autoimmune and several neurodegenerative diseases, and is thus a target for novel therapeutics. One disease that is related to aberrant protein degradation is multiple sclerosis, an autoimmune disorder involving the processing and presentation of myelin autoantigens that leads to the destruction of axons. Here, we show that brain-derived proteasomes from SJL mice with experimental autoimmune encephalomyelitis (EAE) in an ubiquitin-independent manner generate significantly increased amounts of myelin basic protein peptides that induces cytotoxic lymphocytes to target mature oligodendrocytes ex vivo. Ten times enhanced release of immunogenic peptides by cerebral proteasomes from EAE-SJL mice is caused by a dramatic shift in the balance between constitutive and β1i(high) immunoproteasomes in the CNS of SJL mice with EAE. We found that during EAE, β1i is increased in resident CNS cells, whereas β5i is imported by infiltrating lymphocytes through the blood-brain barrier. Peptidyl epoxyketone specifically inhibits brain-derived β1i(high) immunoproteasomes in vitro (kobs/[I] = 240 M(-1)s(-1)), and at a dose of 0.5 mg/kg, it ameliorates ongoing EAE in vivo. Therefore, our findings provide novel insights into myelin metabolism in pathophysiologic conditions and reveal that the β1i subunit of the immunoproteasome is a potential target to treat autoimmune neurologic diseases.
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Alexey
authors: A
authors: Belogurov
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Ekaterina
authors: E
authors: Kuzina
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Anna
authors: A
authors: Kudriaeva
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Alexey
authors: A
authors: Kononikhin
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Sergey
authors: S
authors: Kovalchuk
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Yelena
authors: Y
authors: Surina
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Ivan
authors: I
authors: Smirnov
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Yakov
authors: Y
authors: Lomakin
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Anna
authors: A
authors: Bacheva
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Alexey
authors: A
authors: Stepanov
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Yaroslava
authors: Y
authors: Karpova
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Yulia
authors: Y
authors: Lyupina
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Oleg
authors: O
authors: Kharybin
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Dobroslav
authors: D
authors: Melamed
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Natalia
authors: N
authors: Ponomarenko
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Natalia
authors: N
authors: Sharova
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel.
authors: Eugene
authors: E
authors: Nikolaev
authors: *Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Kazan Federal University, Kazan, Republic of Tatarstan, Russia; Institute of Gene Biology, Russian Acedemy of Sciences, Moscow, Russia; Chemistry Department of Moscow State University, Moscow, Russia; Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia; Institute for Energy Problems of Chemical Physics, Russian Academy of Sciences, Moscow, Russia; Research Institute of Physico-Chemical Medicine, Moscow, Russia; **Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia; Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia; and Assaf Harofeh Medical Center, Zerifin, Israel gabibov@mx.ibch.ru.
authors: Alexander
authors: A
authors: Gabibov
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007124:Immunoenzyme Techniques; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D021122:Protein Subunits; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D004676:Myelin Basic Protein; D021122:Protein Subunits; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: antigen presentation; experimental autoimmune encephalomyelitis; immunoproteasome; multiple sclerosis; oligodendrocytes
references: Cell. 2010 Aug 20;142(4):613-24
references: 20723761
references: Nat Rev Immunol. 2010 Jan;10(1):73-8
references: 20010787
references: Dokl Biochem Biophys. 2013 Nov;453:300-3
references: 24385101
references: Ann Neurol. 1986 Jun;19(6):578-87
references: 3524414
references: J Biol Chem. 1998 Jul 3;273(27):16764-70
references: 9642232
references: PLoS One. 2010;5(2):e9287
references: 20174631
references: Nature. 1988 Jan 14;331(6152):192-4
references: 3277060
references: J Neurosci Res. 2003 Jan 15;71(2):237-45
references: 12503086
references: Mol Cell Proteomics. 2009 Sep;8(9):2090-101
references: 19531498
references: Nature. 1993 Sep 16;365(6443):264-7
references: 8396732
references: J Exp Med. 1962 Apr 1;115:777-88
references: 14461228
references: Proc Natl Acad Sci U S A. 1981 Feb;78(2):761-5
references: 6262770
references: Cell. 1996 May 3;85(3):299-302
references: 8616884
references: Proc Natl Acad Sci U S A. 1990 Oct;87(20):7968-72
references: 1700423
references: Cell. 1994 Sep 9;78(5):761-71
references: 8087844
references: J Neurochem. 2012 May;121(3):486-94
references: 22353035
references: J Immunol. 2008 Jan 15;180(2):1258-67
references: 18178866
references: Brain. 2008 Sep;131(Pt 9):2353-65
references: 18669487
references: FASEB J. 2013 Jan;27(1):222-31
references: 23047895
references: Biochim Biophys Acta. 2014 Sep;1843(9):1942-7
references: 24851840
references: Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4576-9
references: 16537370
references: Lancet. 1974 Jul 13;2(7872):66-9
references: 4137047
references: J Exp Med. 2001 Sep 3;194(5):F27-30
references: 11535639
references: Nature. 1993 Mar 4;362(6415):68-70
references: 7680433
references: Biochem J. 2000 Mar 1;346 Pt 2:447-54
references: 10677365
references: Lancet. 1987 Apr 18;1(8538):893-5
references: 2882294
references: J Exp Med. 2005 Jan 17;201(2):233-40
references: 15657292
references: Chem Biol. 2007 Apr;14(4):419-30
references: 17462577
references: Cell. 2013 Feb 28;152(5):1184-94
references: 23452861
references: J Exp Med. 1991 Jan 1;173(1):19-24
references: 1702137
references: J Immunol. 2010 Apr 15;184(8):4115-22
references: 20228196
references: J Exp Med. 2001 Sep 3;194(5):669-76
references: 11535634
references: J Immunol. 2006 Apr 1;176(7):4075-82
references: 16547243
references: Neurosci Lett. 2006 May 8;398(3):337-42
references: 16472911
references: Immunity. 2012 Jul 27;37(1):134-46
references: 22683122
references: Eur J Immunol. 2008 Sep;38(9):2401-11
references: 18792018
references: Eur J Immunol. 2010 Dec;40(12):3439-49
references: 21108466
references: Am J Pathol. 2009 Sep;175(3):1160-6
references: 19700745
references: Immunity. 1994 Oct;1(7):533-41
references: 7600282
references: Eur J Immunol. 2008 Jul;38(7):1889-99
references: 18506883
references: J Neuroimmunol. 2007 Dec;192(1-2):124-33
references: 17964666
references: Bioessays. 2009 Nov;31(11):1161-71
references: 19795406
references: Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):281-6
references: 16387849
references: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18599-604
references: 20937868
references: J Immunol. 1998 Mar 15;160(6):3056-9
references: 9510211
references: J Immunol. 2012 Aug 15;189(4):1868-77
references: 22772448
references: J Biol Chem. 2014 Jun 20;289(25):17758-66
references: 24739384
references: J Exp Med. 1998 May 18;187(10):1641-6
references: 9584142
references: J Exp Med. 2001 Jun 4;193(11):1319-26
references: 11390439