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Histone deacetylase 4 inhibits NF-κB activation by facilitating IκBα sumoylation
Qi Yang1,2 , Jielin Tang2,3 , Chonghui Xu2,3 , He Zhao2 , Yuan Zhou2 , Yanyi Wang2 , Min Yang1,* , Xinwen Chen2,4 , Jizheng Chen2,*
1Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou 510623, China
2State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
3University of Chinese Academy of Sciences, Beijing 100049, China
4Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
*Correspondence to:Min Yang , Jizheng Chen ,
J Mol Cell Biol, Volume 12, Issue 12, December 2020, 933-945,
Keyword: histone deacetylase 4, sumoylation, IκBα, NF-κB, SUMO E3 ligase

Protein modification by small ubiquitin-like modifier (SUMO) is an important regulatory mechanism for multiple cellular processes. Although the canonical pathway involving the ubiquitylation or phosphorylation of IκBα has been well characterized, little is known about the sumoylation of IκBα 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 IκBα sumoylation. The Cys292 of HDAC4 is a key site for its SUMO E3 ligase activity. The sumoylation of IκBα prevents its polyubiquitination and degradation because 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 IκBα sumoylation. Our work provides insight into mechanisms ensuring optimal mediation of the NF-κB pathway.