Abstract
Immunoproteasomes are known for their involvement in antigen presentation. However, their broad tissue presence and other evidence are indicative of nonimmune functions. We examined a role for immunoproteasomes in cellular responses to the endogenous and environmental carcinogen formaldehyde (FA) that binds to cytosolic and nuclear proteins producing proteotoxic stress and genotoxic DNA-histone crosslinks. We found that immunoproteasomes were important for suppression of a caspase-independent cell death and the long-term survival of FA-treated cells. All major genotoxic responses to FA, including replication inhibition and activation of the transcription factor p53 and the apical ATM and ATR kinases, were unaffected by immunoproteasome inactivity. Immunoproteasome inhibition enhanced activation of the cytosolic protein damage sensor HSF1, elevated levels of K48-polyubiquitinated cytoplasmic proteins and increased depletion of unconjugated ubiquitin. We further found that FA induced the disassembly of 26S immunoproteasomes, but not standard 26S proteasomes, releasing the 20S catalytic immunoproteasome. FA-treated cells also had higher amounts of small activators PA28αβ and PA28γ bound to 20S particles. Our findings highlight the significance of nonnuclear damage in FA injury and reveal a major role for immunoproteasomes in elimination of FA-damaged cytoplasmic proteins through ubiquitin-independent proteolysis.
Highlights
Aging, reactive metabolites and other factors promote formation of misfolded and damaged proteins, which is detrimental to cell functions and is a cause of many neurodegenerative diseases[1]
Acute and chronic FA treatments of normal IMR90 cells produced no significant changes in gene expression of i-proteasomal components (Fig. 1B). These negative results were not caused by technical factors, as IMR90 cells showed a strong upregulation of all three i-proteasomal subunits by interferon-γ (4 ng/ml, 24 h: 3.1 ± 0.4, 49 ± 11.4 and 3.7 ± 0.3-fold for LMP7, LMP2 and LMP10 respectively, n = 3)
DNA-protein crosslinks (DPCs) repair involves a proteolytic removal of crosslinked proteins, which can be performed by a DNA-dependent protease SPRTN in conjunction with DNA replication[40, 41]
Summary
Reactive metabolites and other factors promote formation of misfolded and damaged proteins, which is detrimental to cell functions and is a cause of many neurodegenerative diseases[1]. The 20S core particle contains three active subunits with caspase-, trypsin- and chymotrypsin-like activities These subunits are replaced by related proteases LMP2, LMP10 (MECL1) and LMP7 in immunoproteasomes (i-proteasomes) that are the most abundantly expressed in lymphoid tissues[4, 5]. Expression of i-proteasomes in all major tissues and especially in the immunoprivileged sites, such as the retina[8, 9] and brain[9, 10], points to i-proteasome functions that are different from antigen presentation One of these functions can involve responses to protein-damaging conditions, as evidenced by the upregulation of i-proteasomes by nitric oxide[11] and their role in removal of oxidized proteins[12, 13]. Our findings are important for the mechanistic understanding of FA toxicities, demonstrating that protein damage outside the nucleus contributes to the development of adverse effects
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