Immunoproteasome enhances intracellular proteolysis of myelin basic protein

Kuzina, Ekaterina; Chernolovskaya, E. L.; Kudriaeva, Anna; Zenkova, Marina A.; Knorre, V. D.; Surina, E. A.; Ponomarenko, N. A.; Бобик, Т. В.; Смирнов, Иван; Bacheva, A. V.; Belogurov, Alexey A.; Gabibov, Alexander; Власов, В. В.

doi:10.1134/s1607672913060070

Cited by 18 publications

(12 citation statements)

References 14 publications

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“…The experimental evidence observed here, together with our previous results, suggests that immunoproteasomes equipped by REGa and REGb heptamers became deadly machines, coordinating autoimmune attack on the myelin sheaths ab intra. Our data therefore indirectly support findings that immunoproteasomes and constitutive proteasomes are rather equal in their ability to engage ubiquitinated proteins (63), whereas reported acceleration of protein breakdown by immunoproteasomes in comparison with constitutive proteasomes (64) and evidence that immunoproteasomes degrade basic proteins faster than constitutive proteasome (65,66), particularly, may be explained by the exchange of 19S regulatory particle by REGa and REGb heptamers.…”

Section: Physiologic Relevance Of Reg-mediated Ub-independent Proteassupporting

confidence: 89%

Charge‐mediated proteasome targeting

et al. 2019

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A majority of thousands of intracellular mammalian proteins are recognized by proteasome only being conjugated with ubiquitin (Ub), representing a universal degradation signal operated by the ubiquitination system. Ub‐independent proteasome targeting is rationalized by the existence of 2 types of direct proteasome signals (DPSs), specific amino acid sequences or post‐translational modifications, which are recognized by proteasome regulatory subunits. Historically, the first type was shown to exist in ornithine decarboxylase, whereas acetylation of core histones recently was reported as a second type of DPS. Here we declare a third type, representing charge‐mediated DPS. This discovered DPS may be classified as a monopartite composition‐ but not sequence‐dependent element of ∼70 Å in length enriched in basic and flexible amino acids. This type of degradation signal, which may be provided by cationic chemicals, is most efficiently engaged by proteasomes capped with regulator (REG)α or REGγ in an ATP‐independent manner. Taken together, our findings suggest a novel modality of proteasome‐substrate interrelation bypassing ubiquitination.—Kudriaeva, A., Kuzina, E. S., Zubenko, O., Smirnov, I. V., Belogurov, A. Charge‐mediated proteasome targeting. FASEB J. 33, 6852–6866 (2019). http://www.fasebj.org

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Section: Physiologic Relevance Of Reg-mediated Ub-independent Proteassupporting

confidence: 89%

Charge‐mediated proteasome targeting

et al. 2019

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“…Treatment with both cytokines increased this loss of myelin to ~68%, as would be the expected behavior of an interactive cascade. Furthermore, IFNγ significantly accelerates proteolysis of MBP, 102 suggesting a mechanism for the rapid loss of MBP following SD. Notably, migraine, like SD, occurs with increased OS.…”

Section: Discussionmentioning

confidence: 99%

Spreading depression transiently disrupts myelin via interferon-gamma signaling

Pusic

Mitchell

Kunkler

et al. 2015

Experimental Neurology

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Multiple sclerosis and migraine with aura are clinically correlated and both show imaging changes suggestive of myelin disruption. Furthermore, cortical myelin loss in the cuprizone animal model of multiple sclerosis enhances susceptibility to spreading depression, the likely underlying cause of migraine with aura. Since multiple sclerosis pathology involves inflammatory T cell lymphocyte production of interferon-gamma and a resulting increase in oxidative stress, we tested the hypothesis that spreading depression disrupts myelin through similar signaling pathways. Rat hippocampal slice cultures were initially used to explore myelin loss in spreading depression, since they contain T cells, and allow for controlled tissue microenvironment. These experiments were then translated to the in vivo condition in neocortex. Spreading depression in slice cultures induced significant loss of myelin integrity and myelin basic protein one day later, with gradual recovery by seven days. Myelin basic protein loss was abrogated by T cell depletion, neutralization of interferon-gamma, and pharmacological inhibition of neutral sphingomyelinase-2. Conversely, one day after exposure to interferon-gamma, significant reductions in spreading depression threshold, increases in oxidative stress, and reduced levels of glutathione, an endogenous neutral sphingomyelinase-2 inhibitor, emerged. Similarly, spreading depression triggered significant T cell accumulation, sphingomyelinase activation, increased oxidative stress, and reduction of grey and white matter myelin in vivo. Myelin disruption is involved in spreading depression, thereby providing pathophysiological links between multiple sclerosis and migraine with aura. Myelin disruption may promote spreading depression by enhancing aberrant excitability. Thus, preservation of myelin integrity may provide novel therapeutic targets for migraine with aura.

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“…Recently we have shown that the 26S proteasome can hydrolyze MBP at physiologically relevant concentrations without ubiquitination in vitro and in mature oligodendrocytes [18]. Therefore, proteasome-mediated MBP degradation, which generates myelin antigenic peptides [19, 20], is of a critical importance for the pathogenesis of CNS-related autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

Glatiramer Acetate and Nanny Proteins Restrict Access of the Multiple Sclerosis Autoantigen Myelin Basic Protein to the 26S Proteasome

Kuzina

Kudriaeva

Смирнов

et al. 2014

BioMed Research International

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We recently showed that myelin basic protein (MBP) is hydrolyzed by 26S proteasome without ubiquitination. The previously suggested concept of charge-mediated interaction between MBP and the proteasome led us to attempt to compensate or mimic its positive charge to inhibit proteasomal degradation. We demonstrated that negatively charged actin and calmodulin (CaM), as well as basic histone H1.3, inhibit MBP hydrolysis by competing with the proteasome and MBP, respectively, for binding their counterpart. Interestingly, glatiramer acetate (GA), which is used to treat multiple sclerosis (MS) and is structurally similar to MBP, inhibits intracellular and in vitro proteasome-mediated MBP degradation. Therefore, the data reported in this study may be important for myelin biogenesis in both the normal state and pathophysiological conditions.

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Immunoproteasome enhances intracellular proteolysis of myelin basic protein

Cited by 18 publications

References 14 publications

Charge‐mediated proteasome targeting

Charge‐mediated proteasome targeting

Spreading depression transiently disrupts myelin via interferon-gamma signaling

Glatiramer Acetate and Nanny Proteins Restrict Access of the Multiple Sclerosis Autoantigen Myelin Basic Protein to the 26S Proteasome

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