The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function.
Melanie A SultanaCarmel CluningWai-Sin KwongNicole PolainNathan J PavlosThomas RatajczakJohn P WalshJiake XuSarah L ReaPublished in: PloS one (2021)
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.
Keyphrases
- signaling pathway
- induced apoptosis
- poor prognosis
- oxidative stress
- endoplasmic reticulum stress
- cell cycle arrest
- cell death
- binding protein
- papillary thyroid
- lps induced
- transcription factor
- pi k akt
- small molecule
- wild type
- bone loss
- squamous cell
- bone mineral density
- protein protein
- immune response
- young adults
- single molecule
- amino acid
- dna binding
- drug induced