Macrophage migration inhibitory factor interacts with thioredoxin-interacting protein and induces NF-κB activity.
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. Cys57and Cys81of MIF and Cys36and Cys120of 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.
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
Mi Jeong
MJ
Kim
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
Won Sam
WS
Kim
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
Dong Oh
DO
Kim
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 28644, Republic of Korea.
Jae-Eun
JE
Byun
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
Hangsak
H
Huy
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.
Soo Yun
SY
Lee
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.
Hae Young
HY
Song
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
Young-Jun
YJ
Park
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
Tae-Don
TD
Kim
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
Suk Ran
SR
Yoon
Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
Eun-Ji
EJ
Choi
Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 28644, Republic of Korea.
Hyunjung
H
Ha
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea. Electronic address: haiyoung@kribb.re.kr.
Haiyoung
H
Jung
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea. Electronic address: ipchoi@kribb.re.kr.
Inpyo
I
Choi
D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein / Q000378:metabolism
D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D034741:RNA, Small Interfering; C486715:TXNIP protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D018799:Intercellular Adhesion Molecule-1; D020778:Matrix Metalloproteinase 2
HDAC; HeLa cell; MIF; NF-κB; TXNIP