| Autor: |
Chenliang Zhang, Chen Huang, Hongwei Xia, Huanji Xu, Qiulin Tang, Feng Bi |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Cell Death and Disease, Vol 13, Iss 7, Pp 1-15 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2041-4889 |
| DOI: |
10.1038/s41419-022-05061-8 |
| Popis: |
Abstract Aggresome formation is a protective cellular response to counteract proteasome dysfunction by sequestering misfolded proteins and reducing proteotoxic stress. Autophagic degradation of the protein aggregates is considered to be a key compensating mechanism for balancing proteostasis. However, the precise role of autophagy in proteasome inhibition-induced aggresome biogenesis remains unclear. Herein, we demonstrate that in the early stage of proteasome inhibition, the maturation of the autophagosome is suppressed, which facilitates aggresome formation of misfolded proteins. Proteasome inhibition-induced phosphorylation of SQSTM1 T269/S272 inhibits its autophagic receptor activity and promotes aggresome formation of misfolded proteins. Inhibiting SQSTM1 T269/S272 phosphorylation using Doramapimod aggravates proteasome inhibitor-mediated cell damage and tumor suppression. Taken together, our data reveal a negative effect of autophagy on aggresome biogenesis and cell damage upon proteasome inhibition. Our study suggests a novel therapeutic intervention for proteasome inhibitor-mediated tumor treatment. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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