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.