Putting The Brakes On Inflammation

The protein MST4 has been shown to protect mice from septic shock by dampening inflammation.

AsianScientist (Feb. 9, 2015) – Scientists from the Institute of Biochemistry and Cell Biology (SIBCB) of the Chinese Academy of Sciences have identified a molecular “brake” for inflammation. Their results, published in Nature Immunology, could lead to new anti-inflammatory drugs or treatments for inflammation-driven cancers.

Innate immunity is the first line of defense against pathogens. After detecting pathogen-associated molecular patterns, Toll-like receptors (TLRs) initiate innate immune response via activating the adaptor molecule Tumor necrosis factor receptor associated factor 6 (TRAF6) to remove pathogens.

However, excessive or prolonged inflammatory responses can cause severe host damage or even death, meanwhile chronic inflammation could lead to the development of tumors. The balance between inflammation and tolerance must be fine maintained.

TLR-TRAF6 signaling has been extensively investigated due to its critical role in inflammation and cancer. Yet increasing studies suggest a picture of TLR-TRAF6 pathways far more complicated than previously thought.

In the present study, Professor Zhou Zhaochai and colleages have identified the kinase Mammalian STE20-like protein kinase 4 (MST4) as a “brake” molecule that controls the TLR-TRAF6 pathway, thereby allowing the immune system to dynamically respond to inflammatory stimuli.

By analyzing clinical samples of sepsis and malaria, researchers found that MST4 expression was dysregulated in these infectious diseases. MST4 expression displayed a dramatic fluctuation upon inflammatory stimulation, with its kinetics correlated with the inhibition of inflammatory cytokine production.

The researchers showed that MST4 directly interacts with and phosphorylates TRAF6 to restrict its auto-ubiquitination and signaling activity. Thus MST4 acts as a “brake” on TLR-TRAF6-mediated inflammatory responses. Analyses in mouse model of sepsis confirmed these findings and further revealed that MST4 protects host from septic shock largely through macrophage cells.

This study uncovers new mechanism in controlling innate immunity, and it may also provide new clues to the pathogenesis of some inflammation-related diseases including cancer.

The article can be found at: Jiao et al. (2015) The Kinase MST4 Limits Inflammatory Responses Through Direct Phosphorylation of the Adaptor TRAF6.

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Source: Chinese Academy of Sciences.
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