The putative tumor suppressor Zc3h12d modulates toll-like receptor signaling in macrophages.
Toll-like receptors (TLR) are pivotal in macrophage activation. The molecular mechanisms controlling TLR signaling and macrophage activation are not completely understood. Zc3h12d is originally identified as a possible tumor suppressor gene. However, its function remains unknown. We here report that Zc3h12d negatively regulates TLR signaling and macrophage activation. Zc3h12d was enriched in spleen, lung and lymph node. In macrophages, the expression of Zc3h12d was remarkably induced by TLR ligands through JNK and NF-κB signal pathways. On the other hand, overexpression of Zc3h12d significantly inhibited TLR2 and TLR4 activation-induced JNK, ERK and NF-κB signaling as well as macrophage inflammation. Similar to Zc3h12a/MCPIP1, Zc3h12d also decreased the global cellular protein ubiquitination. These findings suggest that Zc3h12d is a novel negative feedback regulator of TLR signaling and macrophage activation and thus may play a role in host immunity and inflammatory diseases.
Shock/Trauma Research Center & Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, MO 64108, United States.
Shengping
S
Huang
Shock/Trauma Research Center & Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, MO 64108, United States.
Dongfei
D
Qi
Burnett School of Biological Science, College of Medicine, University of Central Florida, Orlando, FL 32816, United States.
Jian
J
Liang
Shock/Trauma Research Center & Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, MO 64108, United States.
Ruidong
R
Miao
Kobe University Graduate School of Medicine, Kobe, Japan.
Kentaro
K
Minagawa
Shock/Trauma Research Center & Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, MO 64108, United States.
Tim
T
Quinn
Kobe University Graduate School of Medicine, Kobe, Japan.
Toshimitsu
T
Matsui
Department of Cell Biology and Anatomy, University of South Carolina, Columbia, SC 29209, United States.
Daping
D
Fan
Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104, United States.
Jianguo
J
Liu
Shock/Trauma Research Center & Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, MO 64108, United States. Electronic address: fum@umkc.edu.
Mingui
M
Fu
D000818:Animals; D018797:Cell Cycle Proteins; D004720:Endonucleases; D004722:Endoribonucleases; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D025461:Feedback, Physiological; D015870:Gene Expression / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination
D018797:Cell Cycle Proteins; D016328:NF-kappa B; D011506:Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D004720:Endonucleases; D004722:Endoribonucleases; C489862:ZC3H12D protein, human; C571148:Zc3h12d protein, mouse