Histone deacetylase 4 inhibits NF-κB activation by facilitating IκBα sumoylation

Protein modification by small ubiquitin-like modifier(SUMO)is an important regulatory mechanism for multiple cellular pro-cesses.Although the canonical pathway involving the ubiquitylation or phosphorylation of IκBα has been well characterized,little is known about the sumoylation of IkBa in the control of NF-κB activity.Here,we find that histone deacetylase 4(HDAC4)negatively regulates tumor necrosis factor-alpha-or lipopolysaccharide-triggered NF-κB activation.HDAC4 belongs to the SUMO E3 ligase family and can directly sumoylate IκBα.The cytoplasm location of HDAC4 is essential for IκBαsumoylation.The Cys292 of HDAC4 is a key site for its SUMO E3 ligase activity.The sumoylation of IkBc prevents its polyubiquitination and degradation be-cause these two modifications occur both at the Lys21.Our findings reveal a previously undiscovered role for HDAC4 in the inflammatory response as a SUMO E3 ligase for IκBαsumoylation.Our work provides insight into mechanisms ensuring optimal mediation of the NF-κB pathway.

Effects of HDAC4 on IL-1β-induced matrix metalloproteinase expression regulated partially through the WNT3A/β-catenin pathway

Background::Histone deacetylase 4(HDAC4)regulates chondrocyte hypertrophy and bone formation.The aim of the present study was to explore the effects of HDAC4 on Interleukin 1 beta(IL-1β)-induced chondrocyte extracellular matrix degradation and whether it is regulated through the WNT family member 3A(WNT3A)/β-catenin signaling pathway.Methods::Primary chondrocytes(CC)and human chondrosarcoma cells(SW1353 cells)were treated with IL-1βand the level of HDAC4 was assayed using Western blotting.Then,HDAC4 expression in the SW1353 cells was silenced using small interfering RNA to detect the effect of HDAC4 knockdown on the levels of matrix metalloproteinase 3(MMP3)and MMP13 induced by IL-1β.After transfection with HDAC4 plasmids,the overexpression efficiency was examined using Real-time quantitative polymerase chain reaction(qRT-PCR)and the levels of MMP3 and MMP13 were assayed using Western blotting.After incubation with IL-1β,the translocation ofβ-catenin into the nucleus was observed using immunofluorescence staining in SW1353 cells to investigate the activation of the WNT3A/β-catenin signaling pathway.Finally,treatment with WNT3A and transfection with glycogen synthase kinase 3 beta(GSK3β)plasmids were assessed for their effects on HDAC4 levels using Western blotting.Results::IL-1βdownregulated HDAC4 levels in chondrocytes and SW1353 cells.Furthermore,HDAC4 knockdown increased the levels of MMP3 and MMP13,which contributed to the degradation of the extracellular matrix.Overexpression of HDAC4 inhibited IL-1β-induced increases in MMP3 and MMP13.IL-1βupregulated the levels of WNT3A,and WNT3A reduced HDAC4 levels in SW1353 cells.GSK-3βrescued IL-1β-induced downregulation of HDAC4 in SW1353 cells.Conclusion::HDAC4 exerted an inhibitory effect on IL-1β-induced extracellular matrix degradation and was regulated partially by the WNT3A/β-catenin signaling pathway.