title: 20S immunoproteasomes remove formaldehyde-damaged cytoplasmic proteins suppressing caspase-independent cell death.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, 02912, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Ortega-Atienza
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, 02912, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Krawic
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, 02912, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Watts
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, 02912, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: McCarthy
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, 02912, USA.
authors.forename: Michal W
authors.initials: MW
authors.lastname: Luczak
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, 02912, USA. anatoly_zhitkovich@brown.edu.
authors.forename: Anatoly
authors.identifier: http://orcid.org/0000-0001-9007-2400
authors.initials: A
authors.lastname: Zhitkovich
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002384:Catalysis; D016923:Cell Death; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D005557:Formaldehyde / Q000737:chemistry / Q000633:toxicity; D015870:Gene Expression; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000276:immunology* / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D013312:Stress, Physiological; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D014452:Ubiquitins; D005557:Formaldehyde; D020169:Caspases; D046988:Proteasome Endopeptidase Complex