Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation
| Autor: | Kerstin Ruoff, Alfred L. Goldberg, Zhe Sha, Helena M. Schnell |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Cell Survival Autophagy-Related Proteins Histone Deacetylase 6 Article Bortezomib 03 medical and health sciences Mice Ubiquitin Cell Line Tumor Sequestosome-1 Protein medicine Autophagy Animals NRF1 RNA Messenger Research Articles Adaptor Proteins Signal Transducing Cell Nucleus Gene knockdown biology Intracellular Signaling Peptides and Proteins Signal transducing adaptor protein Proteins Cell Biology Ubiquitinated Proteins 3. Good health Cell biology 030104 developmental biology Aggresome Proteasome Gene Expression Regulation Proteolysis biology.protein Proteasome inhibitor Small Ubiquitin-Related Modifier Proteins Lysosomes Microtubule-Associated Proteins Proteasome Inhibitors medicine.drug Transcription Factors |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Cells are thought to adapt to proteasome inhibition by using alternative pathways for degradation such as autophagy. Sha et al. now report that cells rapidly induce GABARAPL1 and p62 upon proteasome inhibition, but this promotes cell survival by sequestering ubiquitinated and sumoylated proteins long before the cells induce other Atg genes and activate autophagy. Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of GABARAPL1 (but not other autophagy genes) and p62, which binds ubiquitinated proteins and GABARAPL1 on autophagosomes. Knockdown of p62 or GABARAPL1 reduced cell survival upon proteasome inhibition. p62 induction requires the transcription factor nuclear factor (erythroid-derived 2)-like 1 (Nrf1), which simultaneously induces proteasome genes. After 20-h exposure to proteasome inhibitors, cells activated autophagy and expression of most autophagy genes by an Nrf1-independent mechanism. Although p62 facilitates the association of ubiquitinated proteins with autophagosomes, its knockdown in neuroblastoma cells blocked the buildup of ubiquitin conjugates in perinuclear aggresomes and of sumoylated proteins in nuclear inclusions but did not reduce the degradation of ubiquitinated proteins. Thus, upon proteasome inhibition, cells rapidly induce p62 expression, which enhances survival primarily by sequestering ubiquitinated proteins in inclusions. |
| Databáze: | OpenAIRE |
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