The 11S Proteasome Subunit PSME3 Is a Positive Feedforward Regulator of NF-κB and Important for Host Defense against Bacterial Pathogens.

Abstract

The NF-κB pathway plays important roles in immune responses. Although its regulation has been extensively studied, here, we report an unknown feedforward mechanism for the regulation of this pathway by Toll-like receptor (TLR) ligands in macrophages. During bacterial infections, TLR ligands upregulate the expression of the 11S proteasome subunit PSME3 via NF-κB-mediated transcription in macrophages. PSME3, in turn, enhances the transcriptional activity of NF-κB by directly binding to and destabilizing KLF2, a negative regulator of NF-κB transcriptional activity. Consistent with this positive role of PSME3 in NF-κB regulation and importance of the NF-κB pathway in host defense against bacterial infections, the lack of PSME3 in hematopoietic cells renders the hosts more susceptible to bacterial infections, accompanied by increased bacterial burdens in host tissues. Thus, this study identifies a substrate for PSME3 and elucidates a proteolysis-dependent, but ubiquitin-independent, mechanism for NF-κB regulation that is important for host defense and innate immunity.

• Authors: Jinxia Sun, Yi Luan, Dong Xiang, Xiao Tan, Hui Chen, Qi Deng, Jiaojiao Zhang, Minghui Chen, Hongjun Huang, Weichao Wang, Tingting Niu, Wenjie Li, Hu Peng, Shuangxi Li, Lei Li, Wenwen Tang, Xiaotao Li, Dianqing Wu, Ping Wang
• Journal: Cell reports (Cell Rep) Vol. 14 Issue 4 Pg. 737-749 (Feb 02 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 26776519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Autoantigens
• Ki antigen
• Klf2 protein, mouse
• Kruppel-Like Transcription Factors
• NF-kappa B
• Toll-Like Receptors
• Proteasome Endopeptidase Complex

Topics

• Animals
• Autoantigens (metabolism)
• Bacterial Infections (immunology)
• Feedback, Physiological
• HEK293 Cells
• HeLa Cells
• Humans
• Immunity, Innate
• Kruppel-Like Transcription Factors (metabolism)
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis
• Toll-Like Receptors (metabolism)