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.

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

“…Graphs represent the mean + SEM. *p , 0.05, **p , 0.01, ***p , 0.001. zation (88,89). Overexpressed Smad3 can in turn transactivate the PDGF-B promoter (53), suggesting that one possible way PI3K and Smads positively cooperate for PDGF-B expression in synoviocytes is through an increase in Smad3 protein stability.…”

CYLD downregulation is correlated with tumor development in patients with hepatocellular carcinoma

“…It has been reported that CYLD acts as a negative regulator of the nuclear factor-κB (NF-κB) signaling pathway by deubiquitinating NF-κB essential modulator (NEMO), IκB kinase (IKK)-γ, and IKK upstream regulators, including the tumor necrosis factor (TNF), receptor-associated factor 2 (TRAF2), TRAF6, TRAF7 and receptor-interacting protein 1 (RIP1) (4)(5)(6)(7)(8)(9)(10). CYLD also regulates transforming growth factor-β (TGF-β) signaling via the deubiquitination of Akt in lung fibrosis (11).…”

“…It has been reported that CYLD acts as a negative regulator of the nuclear factor-κB (NF-κB) signaling pathway by deubiquitinating NF-κB essential modulator (NEMO), IκB kinase (IKK)-γ, and IKK upstream regulators, including the tumor necrosis factor (TNF), receptor-associated factor 2 (TRAF2), TRAF6, TRAF7 and receptor-interacting protein 1 (RIP1) (4-10). CYLD also regulates transforming growth factor-β (TGF-β) signaling via the deubiquitination of Akt in lung fibrosis (11).Recent studies have demonstrated that CYLD deficiency may promote the development of several types of cancer in addition to skin tumors caused by mutations and loss of the heterozygosity (LOH) of CYLD. LOH of chromosome 16q, which includes the CYLD gene, has been detected in a large proportion of multiple myeloma cases and has been associated with poor overall survival (12)(13)(14).…”

Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6

“…Therefore, it should be worth investigating the detailed functions of A20 in the canonical TGF-b pathway. A recent report indicated that CYLD decreases stability of Smad3 in a glycogen-synthase kinase3-b (GSK3b)-Hsc70-interacting protein (CHIP)-dependent manner via deubiquitinating Akt in lung fibrotic tissue and mouse lung cells, suggesting that CYLD is a negative regulator of the TGF-b-Smad pathway 52 . However, we did not observe this in CYLD-specific knockdown AML-12 cells, likely due to the differences in cellular context.…”