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

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, Huahao Shen, Kyung-Sun Heo, Haodong Xu, Patricia Bourne, Tomoaki Koga, Haidong Xu, Chen Yan, Binghe Wang, Lin-Feng Chen, Xin-Hua Feng and Jian-Dong Li ()
Additional contact information
Jae Hyang Lim: Center for Inflammation, Georgia State University
Hirofumi Jono: University of Rochester Medical Center
Kensei Komatsu: Center for Inflammation, Georgia State University
Chang-Hoon Woo: College of Medicine, Yeungnam University
Jiyun Lee: Center for Inflammation, Georgia State University
Masanori Miyata: Center for Inflammation, Georgia State University
Takashi Matsuno: Center for Inflammation, Georgia State University
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
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
Jian-Dong Li: Center for Inflammation, Georgia State University

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1776

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