Gal-3BP Negatively Regulates NF-κB Signaling by Inhibiting the Activation of TAK1.

Chang-Soo Hong,Sang-Hee Cho,Joon Haeng Rhee,Jun-Eul Hwang,Wonyoung Choi,Mi-Ra Park,Ik-Joo Chung,Eun-Gene Sun,Woo-Kyun Bae

doi:10.3389/fimmu.2019.01760

Abstract

Galectin-3-binding protein (Gal-3BP) is a member of the family of scavenger receptor cysteine-rich (SRCR) domain-containing proteins, which are associated with the immune system. However, the functional roles and signaling mechanisms of Gal-3BP in host defense and the immune response remain largely unknown. Here, we identified cellular Gal-3BP as a negative regulator of NF-κB activation and proinflammatory cytokine production in lipopolysaccharide (LPS)-stimulated murine embryonic fibroblasts (MEFs). Furthermore, cellular Gal-3BP interacted with transforming growth factor β-activated kinase 1 (TAK1), a crucial mediator of NF-κB activation in response to cellular stress. Gal-3BP inhibited the phosphorylation of TAK1, leading to suppression of its kinase activity and reduced protein stability. In vivo we found that Lgals3BP deficiency in mice enhanced LPS-induced proinflammatory cytokine release and rendered mice more sensitive to LPS-induced endotoxin shock. Overall, these results suggest that Gal-3BP is a novel suppressor of TAK1-dependent NF-κB activation that may have potential in the prevention and treatment of inflammatory diseases.

Highlights

Transforming growth factor β-activated kinase 1 (TAK1) is a key player in controlling nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways that regulate inflammatory and pro-survival signals [1, 2]
Immunoblotting confirmed that Galectin-3-binding protein (Gal-3BP) was not expressed in the spleen, liver and Bone marrowderived macrophages (BMDMs) of the knockout mouse (Figure S1D)
LPS stimulation of KO murine embryonic fibroblasts (MEFs) and BMDMs compared with wile type (WT) cells induced increased secretion of IL-6, TNF-α, and IL-1β according to enzyme-linked immunosorbent assay (ELISA) (Figure 1C and Figure S2A), as well as elevated mRNA expression of these cytokines and chemokines according to RT-PCR (Figure 1D, Figures S2B, S3)

Summary

Introduction

Transforming growth factor β-activated kinase 1 (TAK1) is a key player in controlling nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways that regulate inflammatory and pro-survival signals [1, 2]. TAK1 binding protein 1 (TAB1) binds constitutively to the N-terminus of TAK1, while TAB2 or TAB3 binds to the Cterminus of TAK1, forming a heterotrimeric protein complex composed of either TAK1-TAB1TAB2, or TAK1-TAB1-TAB3 [3,4,5] These adaptor proteins are essential in regulating TAK1 activity, as knockout of these genes is embryonic lethal in mouse models [6,7,8]. TAK1 phosphorylates inhibitor of NF-κB (IκB) kinases (IKKs) and MAPK kinases (MKKs), modulating the activity of the transcription factors NF-κB and AP-1 As these pathways play critical roles in inflammation and cell death, TAK1 functions as an important gatekeeper in fine-tuning cellular responses to extracellular signaling cues [1, 2]

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