Proteasome Composition in Cytokine-Treated Neurons and Astrocytes is Determined Mainly by Subunit Displacement.

Abstract:

:In this study, we investigated if subunit displacement and/or alterations in proteasome biosynthesis are responsible for the changes in the levels of constitutive proteasomes (c-20S), immunoproteasomes (i-20S) and the activators PA28 and PA700 in neurons and astrocytes cultured with a cytokine mixture (IFN-γ/TNF-α/IL-1β). Exposure of both cell types to cytokines for 24 h increases mRNA and protein expression of the i-20S-specific subunit β5i and PA28α/β, and leads to a decline in the amount of the c-20S-specific subunit β5. Since β5 mRNA levels are unchanged by the cytokine treatment, it is fair to conclude that displacement of constitutive β-subunits with inducible β5i subunits is likely the mechanism underlying the decrease in c-20S. As expected, the increase in the amount of the IFN-γ-inducible subunits coincides with elevated expression of phospho-STAT-1 and interferon regulatory factor-1 (IRF-1). However, inhibition of NF-κB signaling in cytokine-treated astrocytes reduces IRF-1 expression without affecting that of i-20S, c-20S and PA28. This suggests that STAT-1 is capable of increasing the transcription of i20S-specific subunits and PA28α/β by itself. The lack of a decrease in proteasome β5 mRNA expression is consistent with the fact that Nrf1 (Nfe2l1) and Nrf2 (Nfe2l2) levels are not reduced by pro-inflammatory cytokines. In contrast, we previously found that there is a significant Nrf1 dysregulation and reduced β5 mRNA expression in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE). Thus, there are stressors in EAE, other than a pro-inflammatory environment, that are not present in cytokine-treated cells.

journal_name

Neurochem Res

journal_title

Neurochemical research

authors

Shanley KL,Hu CL,Bizzozero OA

doi

10.1007/s11064-020-02958-8

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

860-871

issue

4

eissn

0364-3190

issn

1573-6903

pii

10.1007/s11064-020-02958-8

journal_volume

45

pub_type

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