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CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt

Jae Hyang Lim1, Hirofumi Jono, Kensei Komatsu

  • 1Center for Inflammation, Immunity & Infection and Department of Biology, Georgia State University, Atlanta, 30303, USA.

Nature Communications
|April 12, 2012
PubMed

Insights

Deubiquitinase CYLD prevents lung fibrosis by regulating transforming growth factor-β signaling. Loss of CYLD in mice led to lung fibrosis after infection, highlighting CYLD

Area of Science:

  • Pulmonary Medicine
  • Molecular Biology
  • Cellular Biology

Background:

  • Lung injury triggers complex healing responses that, if dysregulated, cause fibrotic lung diseases.
  • Identifying key regulators of lung injury resolution is crucial for preventing fibrosis.
  • Uncontrolled wound healing in the lungs can lead to irreversible tissue damage and functional loss.

Purpose of the Study:

  • To investigate the role of deubiquitinase CYLD in regulating lung injury resolution.
  • To determine if CYLD deficiency contributes to the development of lung fibrosis.
  • To elucidate the molecular mechanisms by which CYLD impacts fibrotic pathways.

Main Methods:

  • Utilized a mouse model infected with Streptococcus pneumoniae to study lung injury.
  • Assessed the impact of CYLD loss on the development of lung fibrosis.
  • Investigated the interaction of CYLD with transforming growth factor-β (TGF-β) signaling components, including Smad3 and Akt.
  • Analyzed the deubiquitination activity of CYLD on Akt and its effect on Smad3 stability.

Main Results:

  • Loss of deubiquitinase CYLD resulted in the development of lung fibrosis in mice following Streptococcus pneumoniae infection.
  • CYLD was found to inhibit transforming growth factor-β signaling, thereby preventing lung fibrosis.
  • CYLD reduces Smad3 stability in an E3 ligase carboxy terminus of Hsc70-interacting protein-dependent manner.
  • CYLD deubiquitinates K63-polyubiquitinated Akt, which contributes to decreased Smad3 stability.

Conclusions:

  • CYLD plays a critical role in the tight regulation of lung injury resolution.
  • CYLD prevents lung fibrosis by modulating Akt and Smad3 stability within the TGF-β signaling pathway.
  • Targeting CYLD may offer a novel therapeutic strategy for preventing or treating lung fibrosis.

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