The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function.
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. Her...
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oai:doaj.org-article:d571449d780e4825a6dc1a441377e9ce2021-12-02T20:04:17ZThe SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function.1932-620310.1371/journal.pone.0259556https://doaj.org/article/d571449d780e4825a6dc1a441377e9ce2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0259556https://doaj.org/toc/1932-6203The 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.Melanie A SultanaCarmel CluningWai-Sin KwongNicole PolainNathan J PavlosThomas RatajczakJohn P WalshJiake XuSarah L ReaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11, p e0259556 (2021) |
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Medicine R Science Q Melanie A Sultana Carmel Cluning Wai-Sin Kwong Nicole Polain Nathan J Pavlos Thomas Ratajczak John P Walsh Jiake Xu Sarah L Rea The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function. |
description |
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. |
format |
article |
author |
Melanie A Sultana Carmel Cluning Wai-Sin Kwong Nicole Polain Nathan J Pavlos Thomas Ratajczak John P Walsh Jiake Xu Sarah L Rea |
author_facet |
Melanie A Sultana Carmel Cluning Wai-Sin Kwong Nicole Polain Nathan J Pavlos Thomas Ratajczak John P Walsh Jiake Xu Sarah L Rea |
author_sort |
Melanie A Sultana |
title |
The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function. |
title_short |
The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function. |
title_full |
The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function. |
title_fullStr |
The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function. |
title_full_unstemmed |
The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function. |
title_sort |
sqstm1/p62 uba domain regulates ajuba localisation, degradation and nf-κb signalling function. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doaj.org/article/d571449d780e4825a6dc1a441377e9ce |
work_keys_str_mv |
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