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Inositol polyphosphate multikinase promotes Toll-like receptor-induced inflammation by stabilizing TRAF6

Eunha Kim1, Jiyoon Beon1, Seulgi Lee1

  • 1Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.

Science Advances
|April 26, 2017
PubMed

Insights

Inositol polyphosphate multikinase (IPMK) stabilizes Toll-like receptor (TLR) signaling mediator TRAF6 protein. IPMK deletion protects mice from sepsis and inflammation by reducing TRAF6 levels and dampening immune responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Toll-like receptor (TLR) signaling is crucial for host defense but requires strict regulation to prevent excessive inflammation.
  • Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a key mediator in TLR pathways, yet the mechanisms controlling its protein stability are not fully understood.

Purpose of the Study:

  • To investigate the role of inositol polyphosphate multikinase (IPMK) in regulating TRAF6 stability and its impact on TLR-induced innate immunity.
  • To elucidate the molecular mechanism by which IPMK influences TRAF6 protein levels and function.

Main Methods:

  • Utilized myeloid-specific knockout mouse models to study IPMK function in vivo.
  • Performed macrophage experiments to assess TRAF6 protein levels and TLR signaling upon IPMK depletion.
  • Investigated the direct interaction between IPMK and TRAF6, including its effect on ubiquitination and proteasomal degradation.

Main Results:

  • Myeloid-specific deletion of IPMK conferred protection against polymicrobial sepsis and lipopolysaccharide-induced inflammation in mice.
  • IPMK depletion in macrophages led to reduced TRAF6 protein levels, consequently dampening TLR-induced signaling and pro-inflammatory cytokine production.
  • IPMK directly binds to TRAF6, stabilizing it by inhibiting K48-linked ubiquitination and proteasomal degradation, independent of its catalytic kinase activity.

Conclusions:

  • IPMK is identified as a critical regulator of TRAF6 stability.
  • IPMK plays a significant physiological role in controlling TLR-induced innate immune responses by modulating TRAF6 protein homeostasis.
Keywords:
Innate immunityTRAF6Toll-like receptorinositol polyphosphate multikinasesepsisubiquitination

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