Journal
FASEB JOURNAL
Volume 29, Issue 5, Pages 1901-1913Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-259333
Keywords
immunoproteasome; antigen presentation; oligodendrocytes; experimental autoimmune encephalomyelitis; multiple sclerosis
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Funding
- Russian Scientific Foundation project Molecular mechanism and physiologic significance of the ubiquitin-independent proteasomal degradation of the proteins [14-14-00585]
- Russian Foundation for Basic Research Grant [13-04-40277-H]
- [CII 2445.2013.4]
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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 beta 1i(high) immunoproteasomes in the CNS of SJL mice with EAE. We found that during EAE, beta 1i is increased in resident CNS cells, whereas beta 5i is imported by infiltrating lymphocytes through the blood-brain barrier. Peptidyl epoxyketone specifically inhibits brain-derived beta 1i(high) immunoproteasomes in vitro (k(obs)/[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 beta 1i subunit of the immunoproteasome is a potential target to treat autoimmune neurologic diseases.
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