Inhibition of NF-κB by MG132 through ER stress-mediated induction of LAP and LIP

• Published in: FEBS letters 2011-07, Vol.585 (14), p.2249-2254
• Main Authors: Nakajima, Shotaro, Kato, Hironori, Takahashi, Shuhei, Johno, Hisashi, Kitamura, Masanori
• Format: Article
• Language: English
• Subjects: Animals; C/EBPβ; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Line; Cysteine Proteinase Inhibitors - pharmacology; Endoplasmic reticulum (ER) stress; Endoplasmic Reticulum - metabolism; Leupeptins - metabolism; Leupeptins - pharmacology; MG132; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB; Rats; Stress, Physiological; Transcriptional Activation; Unfolded Protein Response; Unfolded protein response (UPR)
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2011.05.047

► MG132 suppresses NF-κB through induction of ER stress. ► Through ER stress, MG132 up-regulates C/EBPβ mRNA and causes sustained accumulation of LAP and LIP. ► LAP and LIP mediates inhibition of NF-κB by MG132. Proteasome inhibitor MG132 blocks activation of NF-κB by preventing degradation of IκB. In this report, we propose an alternative mechanism by which MG132 inhibits cytokine-triggered NF-κB activation. We found that MG132 induced endoplasmic reticulum (ER) stress, and attenuation of ER stress blunted the suppressive effect of MG132 on NF-κB. Through ER stress, MG132 up-regulated C/EBPβ mRNA transiently and caused sustained accumulation of its translational products liver activating protein (LAP) and liver-enriched inhibitory protein (LIP), both of which were identified as suppressors of NF-κB. Our results disclosed a novel mechanism underlying inhibition of NF-κB by MG132.