HILI Inhibits TGF-β Signaling by Interacting with Hsp90 and Promoting TβR Degradation

Zhang, Kun; Lu, Yilu; Yang, Ping; Li, Chao; Sun, Huaqin; Tao, Dachang; Zhang, Sizhong; Ma, Yongxin

doi:10.1371/journal.pone.0041973

Cited by 30 publications

(37 citation statements)

References 58 publications

(59 reference statements)

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“…These mutants were cloned into the expression vector pcDNA3.1ϩMyc. Other expression vectors were constructed in our previous report (13). Short hairpin RNA (shRNA) for PIWIL2 (shPIWIL2) was synthesized and cloned into shRNA expression vector pGPU6/GFP/Neo by GenePharma Inc. (Shanghai, People's Republic of China).…”

Section: Methodsmentioning

confidence: 99%

“…Short hairpin RNA (shRNA) for PIWIL2 (shPIWIL2) was synthesized and cloned into shRNA expression vector pGPU6/GFP/Neo by GenePharma Inc. (Shanghai, People's Republic of China). The core sequence (sense strand, 5= CUA UGA GAU UCC UCA ACU ACA GAAG 3=) has been reported in pervious works (12,13,36). For rescue experiments, cells were cotransfected with shPiwil2 and WT Piwil2 expression vector.…”

Section: Methodsmentioning

confidence: 99%

“…HeLa cells and HepG2 cells were maintained in our laboratory as previously described (13). They were cultured in Dulbecco's modified Eagle medium (DMEM)-10% fetal bovine serum (FBS) and transfected by using jetPEI (PolyPlus, Berkeley, CA) according to the manufacturer's protocols.…”

Section: Methodsmentioning

confidence: 99%

“…The human PIWI family is comprised of four different members, Piwil1/Hiwi, Piwil2/Hili, Piwil3, and Piwil4/Hiwi2 (9). The PIWI proteins are expressed predominantly in testis and embryo (1,3,6,9,10), and recently, it has been reported that Piwil2 protein is widely detected in tumors and protects cells from apoptosis (11)(12)(13). Our previous work showed that human Piwil2 inhibits apoptosis by regulating the transforming growth factor beta (TGF-␤) pathway in HEK293 cells and the STAT3/p53 pathway in tumor cells (12,13).…”

mentioning

confidence: 99%

“…The PIWI proteins are expressed predominantly in testis and embryo (1,3,6,9,10), and recently, it has been reported that Piwil2 protein is widely detected in tumors and protects cells from apoptosis (11)(12)(13). Our previous work showed that human Piwil2 inhibits apoptosis by regulating the transforming growth factor beta (TGF-␤) pathway in HEK293 cells and the STAT3/p53 pathway in tumor cells (12,13). Furthermore, Piwil2 also exhibited resistance in response to other forms of stimuli to apoptosis (14)(15)(16).…”

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confidence: 99%

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Piwil2 Inhibits Keratin 8 Degradation through Promoting p38-Induced Phosphorylation To Resist Fas-Mediated Apoptosis

Jiang

Zhao

et al. 2014

Molecular and Cellular Biology

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bThe piwi-like 2 (piwil2) gene is widely expressed in tumors and protects cells from apoptosis induced by a variety of stress stimuli. However, the role of Piwil2 in Fas-mediated apoptosis remains unknown. Here, we present evidence that Piwil2 inhibits Fasmediated apoptosis. By a bacterial two-hybrid screening, we identify a new Piwil2-interacting partner, keratin 8 (K8), a major intermediate filament protein protecting the cell from Fas-mediated apoptosis. Our results show that Piwil2 binds to K8 and p38 through its PIWI domain and forms a Piwil2/K8/P38 triple protein-protein complex. Thus, Piwil2 increases the phosphorylation level of K8 Ser-73 and then inhibits ubiquitin-mediated degradation of K8. As a result, the knockdown of Piwil2 increases the Fas protein level at the membrane. In addition to our previous finding that Piwil2 inhibits the expression of p53 through the Src/ STAT3 pathway, here we demonstrate that Piwil2 represses p53 phosphorylation through p38. Our present study indicates that Piwil2 plays a role in Fas-mediated apoptosis for the first time and also can affect p53 phosphorylation in tumor cells, revealing a novel mechanism of Piwil2 in apoptosis, and supports that Piwil2 plays an active role in tumorigenesis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Piwil2 Inhibits Keratin 8 Degradation through Promoting p38-Induced Phosphorylation To Resist Fas-Mediated Apoptosis

Jiang

Zhao

et al. 2014

Molecular and Cellular Biology

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Cavin‐2 promotes fibroblast‐to‐myofibroblast trans‐differentiation and aggravates cardiac fibrosis

Higuchi,

Ogata,

Nakanishi

et al. 2023

ESC Heart Failure

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AimsTransforming growth factor β (TGF‐β) signalling is one of the critical pathways in fibroblast activation, and several drugs targeting the TGF‐β/Smad signalling pathway in heart failure with cardiac fibrosis are being tested in clinical trials. Some caveolins and cavins, which are components of caveolae on the plasma membrane, are known for their association with the regulation of TGF‐β signalling. Cavin‐2 is particularly abundant in fibroblasts; however, the detailed association between Cavin‐2 and cardiac fibrosis is still unclear. We tried to clarify the involvement and role of Cavin‐2 in fibroblasts and cardiac fibrosis.Methods and resultsTo clarify the role of Cavin‐2 in cardiac fibrosis, we performed transverse aortic constriction (TAC) operations on four types of mice: wild‐type (WT), Cavin‐2 null (Cavin‐2 KO), Cavin‐2flox/flox, and activated fibroblast‐specific Cavin‐2 conditional knockout (Postn‐Cre/Cavin‐2flox/flox, Cavin‐2 cKO) mice. We collected mouse embryonic fibroblasts (MEFs) from WT and Cavin‐2 KO mice and investigated the effect of Cavin‐2 in fibroblast trans‐differentiation into myofibroblasts and associated TGF‐β signalling. Four weeks after TAC, cardiac fibrotic areas in both the Cavin‐2 KO and the Cavin‐2 cKO mice were significantly decreased compared with each control group (WT 8.04 ± 1.58% vs. Cavin‐2 KO 0.40 ± 0.03%, P < 0.01; Cavin‐2flox/flox, 7.19 ± 0.50% vs. Cavin‐2 cKO 0.88 ± 0.44%, P < 0.01). Fibrosis‐associated mRNA expression (Col1a1, Ctgf, and Col3) was significantly attenuated in the Cavin‐2 KO mice after TAC. α1 type I collagen deposition and non‐vascular αSMA‐positive cells (WT 43.5 ± 2.4% vs. Cavin‐2 KO 25.4 ± 3.2%, P < 0.01) were reduced in the heart of the Cavin‐2 cKO mice after TAC operation. The levels of αSMA protein (0.36‐fold, P < 0.05) and fibrosis‐associated mRNA expression (Col1a1, 0.69‐fold, P < 0.01; Ctgf, 0.27‐fold, P < 0.01; Col3, 0.60‐fold, P < 0.01) were decreased in the Cavin‐2 KO MEFs compared with the WT MEFs. On the other hand, αSMA protein levels were higher in the Cavin‐2 overexpressed MEFs compared with the control MEFs (2.40‐fold, P < 0.01). TGF‐β1‐induced Smad2 phosphorylation was attenuated in the Cavin‐2 KO MEFs compared with WT MEFs (0.60‐fold, P < 0.01). Heat shock protein 90 protein levels were significantly reduced in the Cavin‐2 KO MEFs compared with the WT MEFs (0.69‐fold, P < 0.01).ConclusionsCavin‐2 loss suppressed fibroblast trans‐differentiation into myofibroblasts through the TGF‐β/Smad signalling. The loss of Cavin‐2 in cardiac fibroblasts suppresses cardiac fibrosis and may maintain cardiac function.

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Possible role of HIWI2 in modulating tight junction proteins in retinal pigment epithelial cells through Akt signaling pathway

2016

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PIWI subfamily of proteins is shown to be primarily expressed in germline cells. They maintain the genomic integrity by silencing the transposable elements. Although the role of PIWI proteins in germ cells has been documented, their presence and function in somatic cells remains unclear. Intriguingly, we detected all four members of PIWI-like proteins in human ocular tissues and somatic cell lines. When HIWI2 was knocked down in retinal pigment epithelial cells, the typical honeycomb morphology was affected. Further analysis showed that the expression of tight junction (TJ) proteins, CLDN1, and TJP1 were altered in HIWI2 knockdown. Moreover, confocal imaging revealed disrupted TJP1 assembly at the TJ. Previous studies report the role of GSK3β in regulating TJ proteins. Accordingly, phospho-kinase proteome profiler array indicated increased phosphorylation of Akt and GSK3α/β in HIWI2 knockdown, suggesting that HIWI2 might affect TJ proteins through Akt-GSK3α/β signaling axis. Moreover, treating the HIWI2 knockdown cells with wortmannin increased the levels of TJP1 and CLDN1. Taken together, our study demonstrates the presence of PIWI-like proteins in somatic cells and the possible role of HIWI2 in preserving the functional integrity of epithelial cells probably by modulating the phosphorylation status of Akt.

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HILI Inhibits TGF-β Signaling by Interacting with Hsp90 and Promoting TβR Degradation

Cited by 30 publications

References 58 publications

Piwil2 Inhibits Keratin 8 Degradation through Promoting p38-Induced Phosphorylation To Resist Fas-Mediated Apoptosis

Piwil2 Inhibits Keratin 8 Degradation through Promoting p38-Induced Phosphorylation To Resist Fas-Mediated Apoptosis

Cavin‐2 promotes fibroblast‐to‐myofibroblast trans‐differentiation and aggravates cardiac fibrosis

Possible role of HIWI2 in modulating tight junction proteins in retinal pigment epithelial cells through Akt signaling pathway

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