Journal article
The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function
PLoS ONE, Vol.16(11), Art. e0259556
2021
Abstract
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.
Details
- Title
- The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function
- Authors/Creators
- M.A. Sultana (Author/Creator) - Harry Perkins Institute of Medical ResearchC. Cluning (Author/Creator) - Sir Charles Gairdner HospitalW-S Kwong (Author/Creator) - Sir Charles Gairdner HospitalN. Polain (Author/Creator) - Murdoch UniversityN.J. Pavlos (Author/Creator) - The University of Western AustraliaT. Ratajczak (Author/Creator) - Harry Perkins Institute of Medical ResearchJ.P. Walsh (Author/Creator) - Sir Charles Gairdner HospitalJ. Xu (Author/Creator) - The University of Western AustraliaS.L. Rea (Author/Creator) - UWA Centre for Medical Research
- Publication Details
- PLoS ONE, Vol.16(11), Art. e0259556
- Publisher
- Public Library of Science
- Identifiers
- 991005543223007891
- Copyright
- © 2021 Sultana et al.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.80 Bone Diseases
- 1.80.1211 Bisphosphonates
- Web Of Science research areas
- Biochemistry & Molecular Biology
- ESI research areas
- Multidisciplinary