Down-regulation of USP13 mediates phenotype transformation of fibroblasts in idiopathic pulmonary fibrosis

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by fibroblastic foci and progressive scarring of the pulmonary parenchyma. IPF fibroblasts display increased proliferation and enhanced migration and invasion, analogous to cancer cells. This transformation-like phenotype of fibroblasts plays an important role in the development of pulmonary fibrosis, but the mechanism for this is not well understood.MethodsIn this study, we compared gene expression profiles in fibrotic lung tissues from IPF patients and normal lung tissues from patients with primary spontaneous pneumothorax using a cDNA microarray to examine the mechanisms involved in the pathogenesis of IPF. In a cDNA microarray, we found that USP13 was decreased in lung tissues from patients with IPF, which was further confirmed by results from immunohistochemistry and western blot assays. Then, we used RNA interference in MRC-5 cells to inhibit USP13 and evaluated its effects by western blot, real-time RT-PCR, bromodeoxyuridine incorporation, and transwell assays. We also used co-immunoprecipitation and immunofluorescence staining to identify the correlation between USP13 and PTEN in IPF.ResultsUSP13 expression levels were markedly reduced in fibroblastic foci and primary IPF fibroblast lines. The depletion of USP13 resulted in the transformation of fibroblasts into an aggressive phenotype with enhanced proliferative, migratory, and invasive capacities. Additionally, USP13 interacted with PTEN and mediated PTEN ubiquitination and degradation in lung fibroblasts.ConclusionsDown-regulation of USP13 mediates PTEN protein loss and fibroblast phenotypic change, and thereby plays a crucial role in IPF pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0286-3) contains supplementary material, which is available to authorized users.

Follistatin-Like 1 Promotes Bleomycin-Induced Pulmonary Fibrosis through the Transforming Growth Factor Beta 1/Mitogen-Activated Protein Kinase Signaling Pathway

“…Unlike normal lung tissue repair, where fibroblast proliferation is self-limited, PF is characterized by uncontrolled proliferation and migration/invasion of the myofibroblasts and sustained accumulation of ECM. [ 7 ] Distinct phenotypic alterations of the fibroblasts, combined with aberrant ECM production, contribute to the development of PF. [ 8 ] Despite intensive studies, reduplicative epithelial injury along with unremitting ECM deposition seems to involve partly in lung fibrogenesis; however, the precise molecular mechanisms that modulate these processes remain elusive.…”

Ubiquitination and deubiquitination emerge as players in idiopathic pulmonary fibrosis pathogenesis and treatment

“…A recent study from Geng et al showed that loss of PTEN enhances aggressive phenotypes in fibroblasts, resulting in lung fibrosis (94). Interestingly, USP13 was decreased in IPF fibroblasts (94), suggesting a role of USP13 in the pathogenesis of lung fibrosis. USP13 has been shown to regulate energetic metabolism by stabilizing ATP citrate lyase and oxoglutarate dehydrogenase (95).…”

“…PTEN-deficient mice exhibit increased fibroproliferation in response to bleomycin-induced lung fibrosis (93). A recent study from Geng et al showed that loss of PTEN enhances aggressive phenotypes in fibroblasts, resulting in lung fibrosis (94). Interestingly, USP13 was decreased in IPF fibroblasts (94), suggesting a role of USP13 in the pathogenesis of lung fibrosis.…”

The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome

“…NLRP3 [38] Regulates NLRP3 inflammasome activation [38] NF-κB [39], NEMO [33] Regulates NF-κB signaling [33,39] VP24 [49] Involves in virus replication [49] Tat [50] Involves in virus production [50] TRAF3/TRAF6 [51] Modulates antiviral signaling [51] TRAF6/IKKγ [34] Regulates TLR signaling [34] USP-10 CFTR [37,52] Epithelial mucosal clearance [37,52] NICD1 [53] Regulates Notch signaling [53] USP-11 E2F1 [54] Regulates lung epithelia proliferation and wound healing [54] LPA1 [36] Enhances inflammation [36] USP-13 IL-1R8/Sigirr [40] Suppresses lung inflammation [40] PTEN [41] Regulates cell apoptosis [41] MCL1 [42] Regulates transformation of fibroblasts [42] STAT1 [55] Regulates IFN Signaling [55] STING [56] Negatively regulates antiviral responses [56] USP-14 I-kB [31] Increases cytokine release [31] CBP [32] Lung inflammation [32] USP-15 IκBα [57] NF-κB activation [57] USP-17 HDAC2 [58] Reverses glucocorticoid resistance [58] TRAF2/TRAF3 [59] Lung inflammation [59] [92] Inhibits type I IFN signaling and antiviral response [92] POH1 pro-IL-1β [93] Negatively regulates the immune response [93] BRCC3 NLRP3…”

“…The stability of lysophosphatidic acid receptor 1 (LPA1) is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated proinflammatory effects [ 33 , 36 , 37 , 38 , 39 ]. Furthermore, the deubiquitinating enzyme USP13 stabilizes the anti-inflammatory receptor IL-1R8/Sigirr to suppress lung inflammation [ 40 , 41 , 42 ].…”