NEDD4 E3 Ligases: Functions and Mechanisms in Bone and Tooth

Abstract

Protein ubiquitination is a precisely controlled enzymatic cascade reaction belonging to the post-translational modification of proteins. In this process, E3 ligases catalyze the binding of ubiquitin (Ub) to protein substrates and define specificity. The neuronally expressed developmentally down-regulated 4 (NEDD4) subfamily, belonging to the homology to E6APC terminus (HECT) class of E3 ligases, has recently emerged as an essential determinant of multiple cellular processes in different tissues, including bone and tooth. Here, we place special emphasis on the regulatory role of the NEDD4 subfamily in the molecular and cell biology of osteogenesis. We elucidate in detail the specific roles, downstream substrates, and upstream regulatory mechanisms of the NEDD4 subfamily. Further, we provide an overview of the involvement of E3 ligases and deubiquitinases in the development, repair, and regeneration of another mineralized tissue—tooth.

NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases

“…First, E1 activates ubiquitin by attaching to the Cys residue in the tail of the ubiquitin molecule in the ATP energy supply [35]. Then, E1 transfers the activated ubiquitin molecule to E2, which subsequently recognizes the target protein and modifies it through ubiquitination, along with a number of special E3 enzymes [36][37][38] (Figure 1). NEDD4 and NEDD4L are the earliest discovered members of the NEDD4 subfamily and are the most frequently studied proteins for the time being [50].…”

“…NEDD4 and NEDD4L are the earliest discovered members of the NEDD4 subfamily and are the most frequently studied proteins for the time being [50]. NEDD4 and NEDD4L are 900-amino-acid proteins containing several folded structural domains: (1) the N-terminal C2 structural domain, which is a 116-amino-acid calcium-dependent lipid-binding region that plays a role in protein-protein interactions by binding to Ca 2+ to induce the translocation of NEDD4-bound phosphatidylcholine to the plasma membrane [36,51]; (2) the four WW structural domains which recognize PPR motifs and allow for cellular localization and substrate recognition, playing a role in regulating protein-protein interactions [52,53]; (3) the conserved cysteine residue in the structural domain of the C-terminal HECT ubiquitin ligase, which generates an intermediate thioester bond with the active ubiquitin received from E2 and catalyzes the ligase activity of the transfer of Ub from E2 to the substrate [51,54]. NEDD4 and NEDD4L are the earliest discovered members of the NEDD4 subfamily and are the most frequently studied proteins for the time being [50].…”

“…NEDD4 and NEDD4L are the earliest discovered members of the NEDD4 subfamily and are the most frequently studied proteins for the time being [50]. NEDD4 and NEDD4L are 900-amino-acid proteins containing several folded structural domains: (1) the N-terminal C2 structural domain, which is a 116-amino-acid calcium-dependent lipidbinding region that plays a role in protein-protein interactions by binding to Ca 2+ to induce the translocation of NEDD4-bound phosphatidylcholine to the plasma membrane [36,51];…”

Elucidating the role of ubiquitination and deubiquitination in osteoarthritis progression

“…This family includes several members, such as NEDD4, NEDD4-2, WWP1, WWP2, ITCH, Smurf1, Smurf2, NEDL1 and NEDL2. NEDD4 family has been involved in regulation of various diseases, including cancer, inflammation, and osteoarthritis (36)(37)(38). In the following paragraphs, we will discuss the mechanisms of NEDD4 E3 ubiquitin ligases in osteoarthritis initiation and progression (Table 1).…”

Regulation of Ubiquitin Family Signaling in Disease

“…Xu et al [ 9 ] focus on the neuronally expressed developmentally downregulated 4 (NEDD4) subfamily, a subclass of E3 ubiquitin ligases. The authors provide a comprehensive understanding of its specific functions, downstream substrates, and upstream regulatory mechanisms in osteogenesis.…”