Macrophage migration inhibitory factor interacts with thioredoxin-interacting protein and induces NF-κB activity

Abstract

The nuclear factor kappa B (NF-κB) pathway is pivotal in controlling survival and apoptosis of cancer cells. Macrophage migration inhibitory factor (MIF), a cytokine that regulates the immune response and tumorigenesis under inflammatory conditions, is upregulated in various tumors. However, the intracellular functions of MIF are unclear. In this study, we found that MIF directly interacted with thioredoxin-interacting protein (TXNIP), a tumor suppressor and known inhibitor of NF-κB activity, and MIF significantly induced NF-κB activation. MIF competed with TXNIP for NF-κB activation, and the intracellular MIF induced NF-κB target genes, including c-IAP2, Bcl-xL, ICAM-1, MMP2 and uPA, by inhibiting the interactions between TXNIP and HDACs or p65. Furthermore, we identified the interaction motifs between MIF and TXNIP via site-directed mutagenesis of their cysteine (Cys) residues. Cys and Cys of MIF and Cys and Cys of TXNIP were responsible for the interaction. MIF reversed the TXNIP-induced suppression of cell proliferation and migration. Overall, we suggest that MIF induces NF-κB activity by counter acting the inhibitory effect of TXNIP on the NF-κB pathway via direct interaction with TXNIP. These findings reveal a novel intracellular function of MIF in the progression of cancer.

Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway

“…Previous studies have shown that MIF can interact with TXNIP to mitigate the inhibitory effect of TXNIP on NF-kB activity (30)(31)(32). TXNIP has also been shown to be expressed in osteoclasts and regulate RANKL-induced osteoclast formation (33,34).…”

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

“…To elucidate the correlation between TXNIP and AKT, we examined whether TXNIP interacts with AKT in cells. TXNIP‐ and AKT‐overexpressing plasmids were cotransfected into 293T cells, and GST pull‐down assays were performed as previously described (Kim et al, 2017, 2017). TXNIP was found to interact with AKT (Supporting Information Figure S3A), which was also confirmed by immunoprecipitation assays in 293T cells (Figure 3a).…”

“…In our previous reports, we found that TXNIP interacts with p53, p38 MAPK, and macrophage migration inhibitory factor (MIF) and regulates their functional activity (Jung et al, 2016, 2013; Kim et al, 2017). TXNIP stabilized p53 protein via direct interaction, and TXNIP acted as a functional switch of p53 to regulate ROS level in hematopoietic cells.…”

MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics

“…One major action involves MIF binding with JUN-activation domain-binding protein 1 (JAB1), also known as COP9 signalosome subunit 5 (CSN5), through which MIF inhibits JAB1-induced c-Jun-N-terminal kinase (JNK) activity and AP-1 transcriptional activation [27]. Additional protein-binding interactions include thioredoxin-interacting protein (TXNIP), a known NF-κΒ inhibitor [28], and HSP90, which was shown to stabilize MIF in oncogenically transformed cells [29]. …”