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; Jian Dong Li

doi:10.1038/ncomms1776

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

Department of Microbiology

Research output: Contribution to journal › Article › peer-review

94 Scopus citations

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.

Original language	English
Article number	771
Journal	Nature Communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms1776
State	Published - 2012

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Lim, J. H., Jono, H., Komatsu, K., Woo, C. H., Lee, J., Miyata, M., Matsuno, T., Xu, X., Huang, Y., Zhang, W., Park, S. H., Kim, Y. I., Choi, Y. D., Shen, H., Heo, K. S., Xu, H., Bourne, P., Koga, T., Xu, H., ... Li, J. D. (2012). CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt. Nature Communications, 3, [771]. https://doi.org/10.1038/ncomms1776

@article{c79fafa17763456b922d4d7069cd7b88,

title = "CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt",

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.",

author = "Lim, {Jae Hyang} and Hirofumi Jono and Kensei Komatsu and Woo, {Chang Hoon} and Jiyun Lee and Masanori Miyata and Takashi Matsuno and Xiangbin Xu and Yuxian Huang and Wenhong Zhang and Park, {Soo Hyun} and Kim, {Yu Il} and Choi, {Yoo Duk} and Huahao Shen and Heo, {Kyung Sun} and Haodong Xu and Patricia Bourne and Tomoaki Koga and Haidong Xu and Chen Yan and Binghe Wang and Chen, {Lin Feng} and Feng, {Xin Hua} and Li, {Jian Dong}",

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.",

year = "2012",

doi = "10.1038/ncomms1776",

language = "English",

volume = "3",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Lim, JH, Jono, H, Komatsu, K, Woo, CH, Lee, J, Miyata, M, Matsuno, T, Xu, X, Huang, Y, Zhang, W, Park, SH, Kim, YI, Choi, YD, Shen, H, Heo, KS, Xu, H, Bourne, P, Koga, T, Xu, H, Yan, C, Wang, B, Chen, LF, Feng, XH & Li, JD 2012, 'CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt', Nature Communications, vol. 3, 771. https://doi.org/10.1038/ncomms1776

TY - JOUR

T1 - CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt

AU - Lim, Jae Hyang

AU - Jono, Hirofumi

AU - Komatsu, Kensei

AU - Woo, Chang Hoon

AU - Lee, Jiyun

AU - Miyata, Masanori

AU - Matsuno, Takashi

AU - Xu, Xiangbin

AU - Huang, Yuxian

AU - Zhang, Wenhong

AU - Park, Soo Hyun

AU - Kim, Yu Il

AU - Choi, Yoo Duk

AU - Shen, Huahao

AU - Heo, Kyung Sun

AU - Xu, Haodong

AU - Bourne, Patricia

AU - Koga, Tomoaki

AU - Xu, Haidong

AU - Yan, Chen

AU - Wang, Binghe

AU - Chen, Lin Feng

AU - Feng, Xin Hua

AU - Li, Jian Dong

N1 - 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.

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms1776

DO - 10.1038/ncomms1776

M3 - Article

C2 - 22491319

AN - SCOPUS:84860284249

SN - 2041-1723

VL - 3

JO - Nature Communications

JF - Nature Communications

M1 - 771

ER -

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

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