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The putative tumor suppressor Zc3h12d modulates toll-like receptor signaling in macrophages
Shengping Huang1, Dongfei Qi1, Jian Liang2
1Shock/Trauma Research Center & Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, MO 64108, United States.
Abstract:
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.
Insights
Zc3h12d negatively regulates Toll-like receptor (TLR) signaling and macrophage activation. This protein acts as a feedback regulator, impacting host immunity and inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
Background:
- Toll-like receptors (TLR) are crucial for macrophage activation, but the precise molecular mechanisms governing their signaling remain incompletely understood.
- Zc3h12d was initially identified as a potential tumor suppressor, yet its specific biological function has not been elucidated.
Purpose of the Study:
- To investigate the role of Zc3h12d in regulating Toll-like receptor (TLR) signaling and macrophage activation.
- To elucidate the molecular mechanisms underlying Zc3h12d's function in immune responses.
Main Methods:
- Analysis of Zc3h12d expression patterns in various tissues.
- Investigating the induction of Zc3h12d expression by TLR ligands in macrophages via JNK and NF-κB pathways.
- Evaluating the impact of Zc3h12d overexpression on TLR2 and TLR4 signaling pathways (JNK, ERK, NF-κB) and subsequent macrophage inflammatory responses.
- Assessing Zc3h12d's effect on global cellular protein ubiquitination.
Main Results:
- Zc3h12d expression is notably induced by TLR ligands in macrophages through JNK and NF-κB signaling.
- Overexpression of Zc3h12d significantly suppresses TLR2 and TLR4-mediated activation of JNK, ERK, and NF-κB signaling pathways.
- Zc3h12d inhibits TLR-induced macrophage inflammation and reduces global protein ubiquitination, similar to Zc3h12a/MCPIP1.
Conclusions:
- Zc3h12d functions as a novel negative feedback regulator of TLR signaling and macrophage activation.
- Zc3h12d may play a significant role in modulating host immunity and the pathogenesis of inflammatory diseases.
