Ubiquitin-Proteasome System in Periodontitis: Mechanisms and Clinical Implications

Abstract

The progression of periodontitis, a bacteria-driven inflammatory and bone-destructive disease, involves myriad cellular and molecular mechanisms. Protein regulation significantly influences the pathogenesis and management of periodontitis. However, research regarding its regulatory role in periodontitis remains relatively limited. The ubiquitin-proteasome system (UPS), which mainly involves ubiquitination by E3 ubiquitin ligases (E3s) and deubiquitination by deubiquitinating enzymes (DUBs), is the primary intracellular and non-lysosomal mechanism of protein degradation. Recent studies have provided compelling evidence to support the involvement of UPS in periodontitis progression. Increasing evidence indicated that E3s, such as CUL3, Nedd4-2, Synoviolin, FBXL19, PDLIM2, TRIMs and TRAFs, modulate inflammatory responses and bone resorption in periodontitis through multiple classical signalling pathways, including NLRP3, GSDMD, NF-κB, Wnt/β-catenin and Nrf2. Meanwhile, DUBs, including OTUD1, A20, CYLD, UCH-L1 and USPs, also broadly modulate periodontitis progression by regulating signalling pathways such as NF-κB, Wnt/β-catenin, NLRP3, and BMP2. Therefore, the modulation of E3s and DUBs has proven to be an effective therapy against periodontitis. This review provides a comprehensive overview of the regulatory role of ubiquitinating and deubiquitinating enzymes in periodontitis progression and the underlying mechanisms. Finally, we summarise several chemical and genetic methods that regulate UPS enzymes and pave the way for the development of targeted therapies for periodontitis.

Keywords: E3 ubiquitin ligases; bone metabolism; deubiquitinating enzymes; inflammation; periodontitis; ubiquitin‐proteasome system.

FIGURE 1

Ubiquitination and deubiquitination processes within UPS. E1 activates Ub by forming a Ub‐AMP adenylate and transfers Ub to E2. E3 ligase facilitates the transfer of Ub to substrate proteins marked for degradation by the 26S proteasome. DUBs remove Ub chains, regulating degradation and recycling ubiquitin molecules.

FIGURE 2

Effect of E3s on periodontal inflammation and bone resorption. CUL3 induced inflammation through ubiquitinating Gli1 and Keap1 upon P.g‐LPS stimulation. CUL3 induced bone destruction by promoting the ubiquitination of Nrf2 after RANKL stimulation. TRIM16 inhibited bone resorption by promoting the ubiquitination of PICOT and suppressing the ubiquitination of RUNX2 mediated by CHIP. TRIM31 inhibited inflammation by promoting ubiquitination of NLRP10 and NLRP3. PDLIM2 and FBXL19 downregulated RANKL and consequently inhibited bone resorption by promoting the ubiquitination of STAT3 and CREB, respectively. Nedd4‐2 suppressed inflammation through Wnt3a ubiquitination. TRAF2 induced inflammation through ubiquitinating TRAF3 degradation. Synoviolin inhibited inflammation via ubiquitinating GSDMD.

FIGURE 3

Effects of DUBs on periodontal inflammation and bone resorption. UCH‐L1 induced bone resorption by downregulating the mitophagy‐dependent BMP2/Smad signalling pathway and activating the ERK1/2 pathway. USP5 induced inflammation by deubiquitinating STAT3. USP12 escalated inflammation and endoplasmic reticulum stress by modulating the PERK/eIF2α/ATF4 signalling pathway under CTS. A20 suppressed bone resorption by deubiquitinating TRAF6. A20 inhibited inflammation through ubiquitination of NEK7 and deubiquitination of NLRP3 and IL‐17. CYLD negatively regulated p65/NF‐κB signalling triggered by P.g‐LPS. USP17 promoted osteoblast differentiation by stabilising Osterix. USP34 promoted bone formation by increasing Smad1 levels and deubiquitinating RUNX2. OTUD1 inhibited inflammation by deubiquitinating SEC23B.