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Depletion of the 26S proteasome adaptor Ecm29 increases Toll-like receptor 3 signaling

Carlos Gorbea1, Martin Rechsteiner, Jesús G Vallejo

  • 11Division of Cardiology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.

Science Signaling
|October 3, 2013
PubMed

Insights

Depleting extracellular mutant 29 (Ecm29) enhances Toll-like receptor 3 (TLR3) signaling and autophagy. Ecm proteasomes regulate TLR3 trafficking and innate immunity, revealing a new role in immune response attenuation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Toll-like receptor 3 (TLR3) is crucial for recognizing viral double-stranded RNA and initiating innate immune responses.
  • Extracellular mutant 29 (Ecm29) is an adaptor protein associated with a subset of 26S proteasomes, termed Ecm proteasomes.

Purpose of the Study:

  • To investigate the role of Ecm29 and Ecm proteasomes in regulating TLR3 abundance, signaling, and autophagy.
  • To elucidate the impact of Ecm proteasome function on innate immune pathways mediated by TLR3.

Main Methods:

  • Utilized human embryonic kidney-293 and HeLa cells to study protein expression and localization.
  • Assessed the effects of Ecm29 depletion on TLR3, LC3β, p62, tumor necrosis factor receptor-associated factor 3 (TRAF3), and interferon regulatory factor 3 (IRF3) levels.
  • Analyzed TLR3 signaling pathway activation, including kinase phosphorylation and nuclear translocation of transcription factors.

Main Results:

  • Depletion of Ecm29 led to increased abundance of TLR3, LC3β, and p62.
  • Absence of Ecm29 enhanced TLR3 signaling, evidenced by increased TRAF3, enhanced kinase phosphorylation, and IRF3 nuclear localization.
  • Signaling molecules accumulated at juxtanuclear recycling endosomes in Ecm29-depleted cells.

Conclusions:

  • Ecm proteasomes play a novel role in mediating autophagy and regulating the trafficking of TLR3.
  • Ecm proteasomes are involved in the attenuation of TLR3-dependent signaling pathways.
  • These findings uncover a new regulatory mechanism for innate immune responses involving Ecm proteasomes and TLR3.

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