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.
authors.affiliation: Center for Inflammation, Immunity & Infection and Department of Biology, Georgia State University, Atlanta, 30303, USA.
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Kensei
authors.initials: K
authors.lastname: Komatsu
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
authors.forename: Jiyun
authors.initials: J
authors.lastname: Lee
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyata
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuno
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Xu
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Huang
authors.forename: Wenhong
authors.initials: W
authors.lastname: Zhang
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Park
authors.forename: Yu-Il
authors.initials: YI
authors.lastname: Kim
authors.forename: Yoo-Duk
authors.initials: YD
authors.lastname: Choi
authors.forename: Huahao
authors.initials: H
authors.lastname: Shen
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Heo
authors.forename: Haodong
authors.initials: H
authors.lastname: Xu
authors.forename: Patricia
authors.initials: P
authors.lastname: Bourne
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Chen
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011008:Pneumococcal Infections / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; C409984:CYLD protein, human; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases