Autophagic sequestration of SQSTM1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibition
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. Howeve...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05061-8 |
| _version_ | 1818510604988579840 |
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| author | Chenliang Zhang Chen Huang Hongwei Xia Huanji Xu Qiulin Tang Feng Bi |
| author_facet | Chenliang Zhang Chen Huang Hongwei Xia Huanji Xu Qiulin Tang Feng Bi |
| author_sort | Chenliang Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T23:22:16Z |
| format | Article |
| id | doaj.art-8279cea700cb4df680e9e8d4c40c5b7f |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-10T23:22:16Z |
| publishDate | 2022-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-8279cea700cb4df680e9e8d4c40c5b7f2022-12-22T01:29:41ZengNature Publishing GroupCell Death and Disease2041-48892022-07-0113711510.1038/s41419-022-05061-8Autophagic sequestration of SQSTM1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibitionChenliang Zhang0Chen Huang1Hongwei Xia2Huanji Xu3Qiulin Tang4Feng Bi5Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital of Sichuan UniversityDepartment of Medical Oncology, Cancer Center, West China Hospital of Sichuan UniversityLaboratory of Molecular Targeted Therapy in Oncology, West China Hospital of Sichuan UniversityDepartment of Medical Oncology, Cancer Center, West China Hospital of Sichuan UniversityLaboratory of Molecular Targeted Therapy in Oncology, West China Hospital of Sichuan UniversityLaboratory of Molecular Targeted Therapy in Oncology, West China Hospital of Sichuan UniversityAbstract 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.https://doi.org/10.1038/s41419-022-05061-8 |
| spellingShingle | Chenliang Zhang Chen Huang Hongwei Xia Huanji Xu Qiulin Tang Feng Bi Autophagic sequestration of SQSTM1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibition Cell Death and Disease |
| title | Autophagic sequestration of SQSTM1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibition |
| title_full | Autophagic sequestration of SQSTM1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibition |
| title_fullStr | Autophagic sequestration of SQSTM1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibition |
| title_full_unstemmed | Autophagic sequestration of SQSTM1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibition |
| title_short | Autophagic sequestration of SQSTM1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibition |
| title_sort | autophagic sequestration of sqstm1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibition |
| url | https://doi.org/10.1038/s41419-022-05061-8 |
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