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

Author

Listed:
  • Jae Hyang Lim

    (Center for Inflammation, Georgia State University
    University of Rochester Medical Center)

  • Hirofumi Jono

    (University of Rochester Medical Center
    Graduate School of Medical Sciences, Kumamoto University)

  • Kensei Komatsu

    (Center for Inflammation, Georgia State University
    University of Rochester Medical Center)

  • Chang-Hoon Woo

    (College of Medicine, Yeungnam University)

  • Jiyun Lee

    (Center for Inflammation, Georgia State University
    University of Rochester Medical Center)

  • Masanori Miyata

    (Center for Inflammation, Georgia State University
    University of Rochester Medical Center)

  • Takashi Matsuno

    (Center for Inflammation, Georgia State University
    University of Rochester Medical Center)

  • Xiangbin Xu

    (University of Rochester Medical Center)

  • Yuxian Huang

    (Huashan Hospital, Fudan University)

  • Wenhong Zhang

    (Huashan Hospital, Fudan University)

  • Soo Hyun Park

    (College of Veterinary Medicine, Chonnam National University)

  • Yu-Il Kim

    (Internal Medicine)

  • Yoo-Duk Choi

    (Pathology, Chonnam National University & Hospital)

  • Huahao Shen

    (Second Affiliated Hospital, Zhejiang University School of Medicine and State Key Lab of Respiratory Diseases)

  • Kyung-Sun Heo

    (Cardiovascular Research Institute, University of Rochester Medical Center)

  • Haodong Xu

    (University of Rochester Medical Center)

  • Patricia Bourne

    (University of Rochester Medical Center)

  • Tomoaki Koga

    (University of Rochester Medical Center)

  • Haidong Xu

    (Center for Inflammation, Georgia State University
    University of Rochester Medical Center)

  • Chen Yan

    (Cardiovascular Research Institute, University of Rochester Medical Center)

  • Binghe Wang

    (Georgia State University)

  • Lin-Feng Chen

    (College of Medicine, University of Illinois at Urbana-Champaign)

  • Xin-Hua Feng

    (Life Sciences Institute, Zhejiang University
    Baylor College of Medicine)

  • Jian-Dong Li

    (Center for Inflammation, Georgia State University
    University of Rochester Medical Center)

Abstract

Lung injury, whether induced by infection or caustic chemicals, initiates a series of complex wound-healing responses. If uncontrolled, these responses may lead to fibrotic lung diseases and loss of function. Thus, resolution of lung injury must be tightly regulated. The key regulatory proteins required for tightly controlling the resolution of lung injury have yet to be identified. Here we show that loss of deubiquitinase CYLD led to the development of lung fibrosis in mice after infection with Streptococcus pneumoniae. CYLD inhibited transforming growth factor-β-signalling and prevented lung fibrosis by decreasing the stability of Smad3 in an E3 ligase carboxy terminus of Hsc70-interacting protein-dependent manner. Moreover, CYLD decreases Smad3 stability by deubiquitinating K63-polyubiquitinated Akt. Together, our results unveil a role for CYLD in tightly regulating the resolution of lung injury and preventing fibrosis by deubiquitinating Akt. These studies may help develop new therapeutic strategies for preventing lung fibrosis.

Suggested Citation

  • Jae Hyang Lim & Hirofumi Jono & Kensei Komatsu & Chang-Hoon Woo & Jiyun Lee & Masanori Miyata & Takashi Matsuno & Xiangbin Xu & Yuxian Huang & Wenhong Zhang & Soo Hyun Park & Yu-Il Kim & Yoo-Duk Choi , 2012. "CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1776
    DOI: 10.1038/ncomms1776
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