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 β1ihigh 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 β1ihigh immunoproteasomes in vitro (kobs/[I] = 240 M−1s−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.—Belogurov Jr., A., Kuzina, E., Kudriaeva, A., Kononikhin, A., Kovalchuk, S., Surina, Y., Smirnov, I., Lomakin, Y., Bacheva, A., Stepanov, A., Karpova, Y., Lyupina, Y., Kharybin, O., Melamed, D., Ponomarenko, N., Sharova, N., Nikolaev, E., Gabibov, A. Ubiquitin-independent proteosomal degradation of myelin basic protein contributes to development of neurodegenerative autoimmunity.

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

“…BDNF and myelin basic protein, two proteins that have been consistently shown to be decreased in schizophrenia (Martins-de-Souza et al, 2009;Jindal et al, 2010;Green et al, 2011;Zhang et al, 2012) are examples of proteins not degraded through ubiquitin-dependent proteasome activity. BDNF is degraded in the lysosome (Evans et al, 2011) and myelin basic protein can be degraded by metalloproteinases and the proteasome in an ubiquitin-independent manner (Chandler et al, 1995;Belogurov et al, 2015). Accordingly, changes in these and other proteins in schizophrenia are consistent with a model of increased non-26S proteasome degradation.…”

Myelin-derived and putative molecular mimic peptides share structural properties in aqueous and membrane-like environments

“…Finally, although the structural similarity between the MHC II-bound MBP-derived peptides and their molecular mimics, like those from EBV polymerase, can explain how the mimic-specific TCRs in CD4 T cells can recognize self-antigens [84,85], we lack structures of MBP/mimic-bound MHC I complexes. The latter are important, as cytotoxic CD8 T cells can directly attack the oligodendrocytes, which present peptides to them [86]. Neither do we know whether the Fig.…”

“…Note how concentrations above 10 μM decrease turbidity; this is caused by precipitation of the vesicle aggregates generation of T cell tolerance, the amount of MHCloadable non-folded self-peptides is low, but may become significant after inflammatory insult. Interestingly, the presence of autoantigenic MBP peptides in the spectrum of proteasomal products increases after MBP immunization [86]. Secondly, it is possible that mimicspecific, such as Epstein-Barr virus-infected and CNSinfiltrated, memory B cells [91] may have affinity against myelin neoepitopes that are exposed in degenerated/ insulted myelin.…”

“…Nine peptides from four human or mouse compact myelin proteins with a putative autoimmunogenic character and four viral/bacterial peptides suggested [19] to mimic the well-known MS-associated MBP sequence (amino acids [85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] were chosen for structural analysis; all peptides have been described in the literature earlier (see Table 1 and references therein). The corresponding MBP85-99 peptide was a subject of our earlier study [31].…”

Developing Connections among B Lymphocytes and Deregulated Pathways in Autoimmunity

“…The role of Blimp-1 in SLE pathogenesis was discussed by Betty Diamond (Feinstein Institute for Medical Research, Manhasset, NY, USA). The Blimp-1 SLE risk allele exhibits of degradation of autoantigens and for the antigen presentation machinery, thereby contributing to stimulation of the autoimmune processes in MS (27).…”