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 YanBinghe Wang, Lin Feng Chen, Xin Hua Feng, Jian Dong Li

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126 Scopus citations


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.

Original languageEnglish
Article number771
JournalNature Communications
StatePublished - 2012

Bibliographical note

Funding Information:
We are grateful to Drs. R. Bernards, G. Courtois, and J. Massague for kindly providing reagents. This work was supported in part by grants from National Institute of Health DC005843, AI073374 and DC004562 to J.D. Li, AHA 10SDG2630077 to J.H. Lim, CA108454, GM063773, and the National Natural Science Foundation of China (No. 3109360) to X.-H. Feng, HL077789 and HL088400 to C. Yan, the National Natural Science Foundation of China (No. 30825019) to H. Shen, the National Natural Science Foundation of China (No. 30972635) to Y.X. Huang, and the Key Technologies Research and Development Program for Infectious Disease of China (No. 2008ZX10003011) to W.H. Zhang.


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