Houston Methodist. Leading Medicine.
Houston Methodist. Leading Medicine

Immunologists Identify Key Player in Important Immune Response Pathway

Immunologists Identify Key Player in Important Immune Response Pathway

HOUSTON (March 4, 2012) - A crucial part of a healthy immune system is the type 1 interferon signaling pathway, which helps the body fight off viral infections, and also plays an important role in other, more general immune system functions, including innate and adaptive immune responses to invading pathogens.

Proposed model of how NLRP4/DTX4 negatively regulates type I IFN signaling pathways through ubiquitination and degradation of activated TBK1Despite its importance, scientists know little about how the signaling pathway is controlled after vial infection. But in Nature Immunology this week, a group of scientists from The Methodist Hospital Research Institute, the Baylor College of Medicine and Nanjing University, led by TMHRI Center for Inflammation and Epigenetics Director Rongfu Wang, Ph.D., illuminate a key component in that pathway. They report the activation of the type 1 interferon response is influenced by NLRP4, a member of Nod-like receptor protein family that has previously been implicated in biological processes, including innate immune response, inflammation, autoimmune, obesity and cancer.

The activation of the type 1 interferon pathway helps produce proinflammatory cytokines, which can help the immune system attack and clear invading pathogens, but such an innate immune response must be tightly controlled. Otherwise, aberrant or uncontrolled innate immune responses may lead to severe or even fatal consequences and chronic inflammatory diseases. Although many signaling pathways and adaptor molecules converge at TBK1 activation to trigger IRF3-mediated type I IFN signaling and induce its responsive genes, but how activated TBK1 is inhibited remains poorly understood. This study shows that NLRP4 recruits an E3 ubiquitin ligase DTX4 to ubiquitinate the active TBK1, which leads to the proteasomal degradation of kinase TBK1. Nullifying either NLRP4 or DTX4 genes resulted in enhanced phosphorylation of TBK1 and the transcription factor IRF3, thus increasing type 1 interferon signaling and expression of its responsive genes.

"Our results identify a previously unrecognized role for NLRP4 in the regulation of type I interferon signaling and provide molecular insight into the mechanisms of maintaining innate immune homeostasis in response to viral infection," Wang and coauthors write.

A paper co-written by Wang in the January issue of Immunity reported that TAK1, the protein kinase that plays a critical role in activating B- and T-cells during an immune response, appears to have the opposite effect on myeloid cells, suppressing NF-kB and MAP kinase p38 in neutrophils. It was the first time that the kinase had been shown to exert opposite effects on a phosphorylation signaling cascade depending on cell type.

Research described in the Nature Immunity paper was supported by the National Natural Science Foundation of China, the National Cancer Institute, the Cancer Research Institute, and The Methodist Hospital Research Institute. Also contributing to this research were Jun Cui, Yinyin Li, and Helen Wang (TMHRI), and Liang Zhu, Dan Liu, and Zhou Songyang (Baylor College of Medicine).

To speak with Dr. Wang or a representative of TMHRI, please contact David Bricker, The Methodist Hospital, at 832-667-5811 or dmbricker@houstonmethodist.org.  For more information on The Methodist Hospital Research Institute, visit our website. Follow Methodist on Facebook and Twitter.