Publication
The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function
Publisher:
Public Library of Science (PLoS)
Date:
04-11-2021
DOI:
10.1371/JOURNAL.PONE.0259556
Abstract: The LIM-domain containing protein Ajuba and the scaffold protein SQSTM1 62 regulate signalling of NF-κB, a transcription factor involved in osteoclast differentiation and survival. The ubiquitin-associated domain of SQSTM1 62 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 62 inhibits this activation in an UBA domain-dependent manner. SQSTM1 62 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 62 (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 62 reduces the amount of Ajuba present in the nucleus. SQSTM1 62 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 62 expression, such as osteoclasts in Paget’s disease of bone and various cancers, SQSTM1 62 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 62 observed in cancer may enhance Ajuba-mediated cancer cell survival.