The adaptor protein p62/SQSTM1 in osteoclast signaling pathways

Abstract

Paget's disease of bone (PDB) is a skeletal disorder characterized by focal and disorganized increases in bone turnover and overactive osteoclasts. The discovery of mutations in the SQSTM1/p62 gene in numerous patients has identified protein p62 as an important modulator of bone turnover. In both precursors and mature osteoclasts, the interaction between receptor activator of NF-κB ligand (RANKL) and its receptor RANK results in signaling cascades that ultimately activate transcription factors, particularly NF-κB and NFATc1, promoting and regulating the osteoclast differentiation, activity, and survival. As a scaffold with multiple protein-protein interaction motifs, p62 is involved in virtually all the RANKL-activated osteoclast signaling pathways, along with being implicated in numerous other cellular processes. The p62 adaptor protein is one of the functional links reported between RANKL and TRAF6-mediated NF-κB activation, and also plays a major role as a shuttling factor that targets polyubiquitinated proteins for degradation by either the autophagy or proteasome pathways. The dysregulated expression and/or activity of p62 in bone disease up-regulates osteoclast functions. This review aims to outline and summarize the role of p62 in RANKL-induced signaling pathways and in ubiquitin-mediated signaling in osteoclasts, and the impact of PDB-associated p62 mutations on these processes.

Further Evidence of Contrasting Phenotypes Caused by Reciprocal Deletions and Duplications: Duplication of NSD1 Causes Growth Retardation and Microcephaly

“…MAPK9 encodes a kinase involved in signal transduction pathways that is required for late-stage differentiation of osteoblasts and overexpression of which causes increased mineral deposition in bone [Matsuguchi et al, 2009]. Additional genes in the region may also play roles in bone formation, including HNRNPAB [Fomenkov et al, 2003], ADAMTS2 [Bar-Yosef et al, 2008] and SQSTM1 [Chamoux et al, 2009;McManus and Roux, 2012], although there is insufficient literature to support a direct mechanism of a copy gain of these genes. Finally, it is possible that subject 8's craniosynostosis is secondary to her microcephaly, and duplication of one or more genes distal to NSD1 causes microcephaly, as opposed to causing craniosynostosis.…”

Glucocorticoids: Dose-related effects on osteoclast formation and function via reactive oxygen species and autophagy

“…To assess the intensity of autophagy flux activity, degradation of p62/SQSTM1, the substrate of autophagy [32], and lipidation of LC3 (conversion of LC3-I into LC3-II) were analyzed by western blot. Dex led to down-regulated p62 and up-regulated LC3-II which signified stronger autophagy flux activity (Fig.…”

Role of p62/SQSTM1 in liver physiology and pathogenesis

“…Because of its unique binding to ubiquitinated proteins together with its ability to bind LC3, p62 has been demonstrated to be an important receptor protein for selective autophagic clearance of ubiquitinated protein aggregates and organelles 5, 9 . The importance of the UBA domain of p62 has also been underscored by the findings that mutations of the UBA domain are frequently associated with familial and sporadic Paget’s disease of bone, which is a chronic and metabolic disorder characterized by increased bone turnover 39–41 . It is well known that RANKL and its receptor RANK play an important role in regulating osteoclast differentiation, activity, and survival by activating NF-κB 6 .…”

“…It has been suggested that p62 forms a complex with TRAF-6 and aPKC, which is critical for RANKL-induced NF-κB activation 6, 42, 43 . Mutations in the UBA domain results in loss of UBA function and also activate TRAF6–NF-kB signaling, which results in increased osteoclastogenesis 8, 39, 44 . p62 KO mice also show a similar phenotype reminiscent of Paget’s disease with impaired NF-κB activation 6 , further supporting that p62 is an important mediator regulating bone homeostasis.…”