Study Identifies the Novel Molecular Signal for Triggering Septic Shock

(Figure: Deletion of IPMK (inositol polyphosphate multikinase) in macrophages reduces the stability of TRAF6 protein which is the key to innate immune signaling, thereby blocking excessive inflammation in response to pathological bacterial infection.)

Professor Seyun Kim’s team at the Department of Biological Sciences reported the mechanism by which cellular signaling transduction networks are precisely controlled in mediating innate immune responses, such as sepsis, by the enzyme IPMK (Inositol polyphosphate multikinase) which is essential for inositol biosynthesis metabolism.

In collaboration with Professor Hyun Seong Roh at Seoul National University, the study’s first author, Eunha Kim, a Ph.D. candidate in Department of Biological Sciences, performed a series of cellular, biochemical, and physiological experiments searching for the new function of IPMK enzymes in macrophages. The research findings were published in Science Advances on April 21.

Professor Kim’s team has been investigating various inositol metabolites and their biosynthesis metabolism for several years and has multilaterally identified the signaling actions of IPMK  for controlling cellular growth and energy homeostasis.

This research showed that the specific deletion of IPMK enzymes in macrophages could significantly reduce levels of inflammation and increase survival rates in mice when they were challenged by microbial septic shock and endotoxins. This suggests a role for IPMK enzymes in mediating innate inflammatory responses that are directly related to a host’s defense against pathogenic bacterial infection.

The team further discovered that IPMK enzymes directly bind to TRAF6 proteins, a key player in immune signaling, thus protecting TRAF6 proteins from ubiquitination reactions that are involved in protein degradation. In addition, Kim and his colleagues successfully verified this IPMK-dependent immune control by employing short peptides which can specifically interfere with the binding between IPMK enzymes and TRAF6 proteins in macrophage cells.

This research revealed a novel function of IPMK enzymes in the fine tuning of innate immune signaling networks, suggesting a new direction for developing therapeutics targeting serious medical conditions such as neuroinflammation, type 2 diabetes, as well as polymicrobial sepsis that are developed from uncontrolled host immune responses. This research was funded by the Ministry of Science, ICT and Future Planning.