The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates
| Autor: | Mena Abdel-Nour, Jennifer L. Gommerman, Stephen E. Girardin, Valeria Ramaglia, Tapas Mukherjee, J J Chen, Lorraine V. Kalia, Hien Chau, Dana J. Philpott, Suneil K. Kalia, Jessica Tsalikis, Athanasia A. Bianchi, Damien Arnoult |
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| Přispěvatelé: | INSERM U1197 |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
ATF4 activating transcription factor 4 CASA chaperone-assisted selective autophagy CASA alpha-synuclein Parkinson's disease Protein aggregation BAG3-HSPB8 complex Biochemistry Mice eIF-2 Kinase 0302 clinical medicine SC scramble sequence BAG3 B-cell lymphoma-2 associated athanogene 3 protein misfolding unfolded protein response (UPR) ComputingMilieux_MISCELLANEOUS Heat-Shock Proteins cUPR cytosolic unfolded protein response Mice Knockout 0303 health sciences Microglia Chaperone-assisted selective autophagy Chemistry BAG3–HSPB8 complex HSPB8 heat shock protein 8 Cell biology Parkinson disease medicine.anatomical_structure Aggresome Spinal Cord HSP heat shock protein eIF2alpha Research Article Programmed cell death autophagy [SDV.BC]Life Sciences [q-bio]/Cellular Biology Protein Serine-Threonine Kinases BAG3 Integrated Stress Response protein aggregation Protein Aggregates 03 medical and health sciences synuclein medicine Animals Humans Molecular Biology Adaptor Proteins Signal Transducing 030304 developmental biology ISR integrated stress response 030102 biochemistry & molecular biology Autophagy Cell Biology Cytosol 030104 developmental biology Proteostasis shHRI small hairpin RNA directed against HRI sequence HEK293 Cells HRI proteasome Proteotoxicity ubiquitin-dependent protease Parkinson’s disease Unfolded Protein Response Unfolded protein response Apoptosis Regulatory Proteins HRI heme-regulated inhibitory 030217 neurology & neurosurgery HeLa Cells Molecular Chaperones |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2020, pp.jbc.RA120.014415. ⟨10.1074/jbc.RA120.014415⟩ The Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2021, 296, pp.100050. ⟨10.1074/jbc.RA120.014415⟩ |
| ISSN: | 0021-9258 1083-351X |
| DOI: | 10.1074/jbc.RA120.014415⟩ |
| Popis: | Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system, and defective clearance of these protein aggregates results in proteotoxicity and cell death. Recently, we found that the eIF2α kinase heme-regulated inhibitory (HRI) induced a cytosolic unfolded protein response to prevent aggregation of innate immune signalosomes, but whether HRI acts as a general sensor of proteotoxicity in the cytosol remains unclear. Here we show that HRI controls autophagy to clear cytosolic protein aggregates when the ubiquitin-proteasome system is inhibited. We further report that silencing the expression of HRI resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy, suggesting that HRI may control proteostasis in the cytosol at least in part through chaperone-assisted selective autophagy. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of overexpressed α-synuclein, a protein known to aggregate in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In agreement with these data, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month-old Hri-/- mice as compared with Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response that could be leveraged to bolster the clearance of cytotoxic protein aggregates. |
| Databáze: | OpenAIRE |
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