Decreased levels of constitutive proteasomes in experimental autoimmune encephalomyelitis may be caused by a combination of subunit displacement and reduced Nfe2l1 expression

Abstract

The goal of this study was to determine if subunit displacement and/or alterations in proteasome biosynthesis could explain the changes observed in the levels of constitutive proteasomes (c‐20S) and immunoproteasomes (i‐20S) in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE). To this end, EAE was induced in C57BL/6 mice by immunization with MOG35–55 peptide. Spinal cords were collected at different times during the disease course and used for western blotting, RNA analysis, and immunohistochemistry. The results show that, as expression of i‐20S and the activator PA28 rise in EAE, there is a concomitant decline in that of c‐20S at the mRNA and protein level. These changes are observed in neurons and astrocytes but not in oligodendrocytes. The increased amounts of the i‐20S‐specific subunit β5i and PA28α/β in EAE correlate with the levels of interferon‐γ and its downstream effectors p‐signal transducer and activator of transcription 1 and interferon regulatory factor‐1, but not with those of nuclear factor kappa‐light‐chain‐enhancer of activated B cells. This suggests that the signal transducer and activator of transcription 1/interferon regulatory factor‐1 pathway is solely responsible for the induction of these subunits. The decrease in the mRNA and protein levels corresponding to the c‐20S‐specific subunit β5 may also be due to reduced expression of the nuclear factor (erythroid‐derived 2)‐like‐1 (Nrf1 or Nfe2l1), specifically Nrf1α and Nrf1β. Low Nfe2l1 mRNA expression is unlikely caused by reduced mammalian target of rapamycin signaling but could be the result of diminished pre‐B‐cell leukemia homeobox‐1 transcription factor levels. Together, these findings suggest that a combination of subunit displacement and reduced Nrf1 expression may be responsible for c‐20S impairment in EAE. The present work provides insights into the dynamics of proteasome expression in the CNS of EAE mice and is the first to explore Nrf1 signaling in an inflammatory demyelinating disorder.

Metabolic signature and proteasome activity controls synovial migration of CDC42hiCD14+ cells in rheumatoid arthritis

“…NFE2L1 and its paralog NFE2L3 maintain the basal proteasome activity, while the simultaneous deletion of those proteins impairs proteasome function in cancer (39,63). Acting through the downregulation of NFE2L1, autoimmune inflammation induces t h e p r o t e a s o m e s u b u n i t d i s p l a c e m e n t f o r m i n g t h e immunoproteasome (64). In this study, we found that the experimental hypoxia suppressed the mRNA levels of NFE2L1 and let IFNg activate the transcription of the proteasome subunits in CD14 + cells, while the exposure to JAKi upregulated NFE2L1, which decreased immunoproteasome production.…”

Metabolic signature and proteasome activity controls synovial migration ofCDC42hiCD14+cells in rheumatoid arthritis

“…NFE2L1 and its paralog NFE2L3 maintain the basal proteasome activity, while simultaneous deletion of those proteins impairs proteasome function in cancer cells 39,63 . Acting through down-regulation of NFE2L1, autoimmune inflammation has been shown to trigger the subunit displacement in S26 proteasome complex forming the immunoproteasome 64 . Indeed, we found that experimental hypoxia suppressed mRNA levels of NFE2L1 in CD14 + cells having no significant effect on the metabolic signature.…”

NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases

“…In animal model, experimental autoimmune encephalomyelitis (EAE) is widely used for autoimmune disorders of the central nervous system, particularly multiple sclerosis, in which proteasomal types show two distinctive and even opposite responses: constitutive proteasome (i.e., c-proteasome) levels decrease, while immunoproteasome (i.e., i-proteasome) levels rise [ 90 , 91 ]. A study by Shanley et al suggests that the changes in c-proteasome may be just due to reduced expression of NFE2L1, but their subsequent work further showed that this reduction is likely not attributable to pro-inflammatory cytokine exposure [ 91 , 92 ]. However, the exact cause of this effect remains unknown to date, although it may be quite informative to assess if reversing NFE2L1-lowered levels could negate the phenotype of EAE.…”