The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function
| العنوان: | The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function |
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| المؤلفون: | Nicole Polain, Wai Sin Kwong, Thomas Ratajczak, Sarah L. Rea, John P. Walsh, Carmel Cluning, Melanie A. Sultana, Jiake Xu, Nathan J. Pavlos |
| المصدر: | PLoS ONE PLoS ONE, Vol 16, Iss 11, p e0259556 (2021) PLoS ONE, Vol 16, Iss 11 (2021) |
| بيانات النشر: | Public Library of Science, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Scaffold protein, Gene Expression, Osteoclasts, Biochemistry, Cell Signaling, Animal Cells, Sequestosome-1 Protein, Medicine and Health Sciences, Musculoskeletal System, Connective Tissue Cells, Multidisciplinary, Cell Death, Chemistry, NF-kappa B, Cell biology, medicine.anatomical_structure, Oncology, Cell Processes, Connective Tissue, Medicine, Anatomy, Cellular Types, Cellular Structures and Organelles, Research Article, Signal Transduction, Protein Binding, Signal Inhibition, Science, Autophagic Cell Death, Blotting, Western, Signaling Complexes, DNA construction, Transfection, Research and Analysis Methods, Osteoclast, DNA-binding proteins, medicine, Genetics, Humans, Immunoprecipitation, Gene Regulation, Molecular Biology Techniques, Bone, Transcription factor, Molecular Biology, Skeleton, Autophagy, HEK 293 cells, Wild type, Biology and Life Sciences, Proteins, Cancers and Neoplasms, Cell Biology, Regulatory Proteins, Biological Tissue, HEK293 Cells, Cell Signaling Structures, Cancer cell, Plasmid Construction, Protein Ajuba, Transcription Factors |
| الوصف: | The LIM-domain containing protein Ajuba and the scaffold protein SQSTM1/p62 regulate signalling of NF-κB, a transcription factor involved in osteoclast differentiation and survival. The ubiquitin-associated domain of SQSTM1/p62 is frequently mutated in patients with Paget’s disease of bone. Here, we report that Ajuba activates NF-κB activity in HEK293 cells, and that co-expression with SQSTM1/p62 inhibits this activation in an UBA domain-dependent manner. SQSTM1/p62 regulates proteins by targeting them to the ubiquitin-proteasome system or the autophagy-lysosome pathway. We show that Ajuba is degraded by autophagy, however co-expression with SQSTM1/p62 (wild type or UBA-deficient) protects Ajuba levels both in cells undergoing autophagy and those exposed to proteasomal stress. Additionally, in unstressed cells co-expression of SQSTM1/p62 reduces the amount of Ajuba present in the nucleus. SQSTM1/p62 with an intact ubiquitin-associated domain forms holding complexes with Ajuba that are not destined for degradation yet inhibit signalling. Thus, in situations with altered levels and localization of SQSTM1/p62 expression, such as osteoclasts in Paget’s disease of bone and various cancers, SQSTM1/p62 may compartmentalize Ajuba and thereby impact its cellular functions and disease pathogenesis. In Paget’s, ubiquitin-associated domain mutations may lead to increased or prolonged Ajuba-induced NF-κB signalling leading to increased osteoclastogenesis. In cancer, Ajuba expression promotes cell survival. The increased levels of SQSTM1/p62 observed in cancer may enhance Ajuba-mediated cancer cell survival. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ee93e9958c607c911933faee42d8c064 http://europepmc.org/articles/PMC8568271 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ee93e9958c607c911933faee42d8c064 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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