USP15 promotes pulmonary vascular remodeling in pulmonary hypertension in a YAP1/TAZ-dependent manner
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Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disease characterized by pulmonary vascular remodeling. Excessive growth and migration of pulmonary artery smooth muscle cells (PASMCs) are believed to be major contributors to pulmonary vascular remodeling. Ubiquitin-specific protease 15 (USP15) is a vital deubiquitinase that has been shown to be critically involved in many pathologies. However, the effect of USP15 on PH has not yet been explored. In this study, the upregulation of USP15 was identified in the lungs of PH patients, mice with SU5416/hypoxia (SuHx)-induced PH and rats with monocrotaline (MCT)-induced PH. Moreover, adeno-associated virus-mediated functional loss of USP15 markedly alleviated PH exacerbation in SuHx-induced mice and MCT-induced rats. In addition, the abnormal upregulation and nuclear translocation of YAP1/TAZ was validated after PH modeling. Human pulmonary artery smooth muscle cells (hPASMCs) were exposed to hypoxia to mimic PH in vitro, and USP15 knockdown significantly inhibited cell proliferation, migration, and YAP1/TAZ signaling in hypoxic hPASMCs. Rescue assays further suggested that USP15 promoted hPASMC proliferation and migration in a YAP1/TAZ-dependent manner. Coimmunoprecipitation assays indicated that USP15 could interact with YAP1, while TAZ bound to USP15 after hypoxia treatment. We further determined that USP15 stabilized YAP1 by inhibiting the K48-linked ubiquitination of YAP1. In summary, our findings reveal the regulatory role of USP15 in PH progression and provide novel insights into the pathogenesis of PH.
Abstract
Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disease characterized by pulmonary vascular remodeling. Excessive growth and migration of pulmonary artery smooth muscle cells (PASMCs) are believed to be major contributors to pulmonary vascular remodeling. Ubiquitin-specific protease 15 (USP15) is a vital deubiquitinase that has been shown to be critically involved in many pathologies. However, the effect of USP15 on PH has not yet been explored. In this study, the upregulation of USP15 was identified in the lungs of PH patients, mice with SU5416/hypoxia (SuHx)-induced PH and rats with monocrotaline (MCT)-induced PH. Moreover, adeno-associated virus-mediated functional loss of USP15 markedly alleviated PH exacerbation in SuHx-induced mice and MCT-induced rats. In addition, the abnormal upregulation and nuclear translocation of YAP1/TAZ was validated after PH modeling. Human pulmonary artery smooth muscle cells (hPASMCs) were exposed to hypoxia to mimic PH in vitro, and USP15 knockdown significantly inhibited cell proliferation, migration, and YAP1/TAZ signaling in hypoxic hPASMCs. Rescue assays further suggested that USP15 promoted hPASMC proliferation and migration in a YAP1/TAZ-dependent manner. Coimmunoprecipitation assays indicated that USP15 could interact with YAP1, while TAZ bound to USP15 after hypoxia treatment. We further determined that USP15 stabilized YAP1 by inhibiting the K48-linked ubiquitination of YAP1. In summary, our findings reveal the regulatory role of USP15 in PH progression and provide novel insights into the pathogenesis of PH.
참고문헌 (48)
- Galie, N., "2015 ESC", ERS Guidelines for the diagnosis and treatment of pulmonary hypertension : the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology(ESC)and the European Respiratory Society(ERS) : Endorsed by : Association for European Paediatric and Congenital Cardiology(AEPC), International Society for Heart and Lung Transplantation(ISHLT), 2016, pp.37, 67~119
- Wijeratne, D. T., "Increasing incidence and prevalence of world health organization groups 1 to 4 pulmonary hypertension : a population-based cohort study in Ontario, Canada", Circ. Cardiovasc. Qual. Outcomes, 11, pp.e003973~ (2018)
- He, Y., "Loss of DP1 aggravates vascular remodeling in pulmonary arterial hypertension via mTORC1 signaling", Am. J. Respir. Crit. Care Med, 201, pp.1263~1276 (2020)
- Bisserier, M., "Current and emerging therapeutic approaches to pulmonary hypertension", Rev. Cardiovasc. Med, 21, pp.163~179 (2020)
- Runo, J. R., "Primary pulmonary hypertension", Lancet, 361, pp.1533~1544 (2003)
- Bertero, T., "Vascular stiffness mechanoactivates YAP", TAZ-dependent glutaminolysis to drive pulmonary hypertension, 2016, pp.126, 3313~3335
- Zhang, L., "Blockade of JAK2 protects mice against hypoxia-induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation", Cell Prolif, 53, pp.e12742~ (2020)
- Chen, J., "Mechanosensitive channel Piezo1 is required for pulmonary artery smooth muscle cell proliferation", Am. J. Physiol. Lung Cell Mol. Physiol, 322, pp.L737~L760 (2022)
- Chou, C. K., "The regulations of deubiquitinase USP15 and its pathophysiological mechanisms in diseases", Int. J. Mol. Sci, 18, pp.483~ (2017)
- Das, T., "USP15 and USP4 facilitate lung cancer cell proliferation by regulating the alternative splicing of SRSF1", Cell Death Discov, 8, pp.24~ (2022)
- Zou, Q., "USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses", Nat. Immunol, 15, pp.562~570 (2014)
- Cornelissen, T., "The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy", Hum. Mol. Genet, 23, pp.5227~5242 (2014)
- Wang, W., "Positive feedback regulation between USP15 and ERK2 inhibits osteoarthritis progression through TGF-β", SMAD2 signaling, 2021, pp.23, 84~
- Tu, L., "USP15 enhances the proliferation, migration, and collagen deposition of hypertrophic scar-derived fibroblasts by deubiquitinating TGF-βR1 in vitro", Plast. Reconstr. Surg, 148, pp.1040~1051 (2021)
- Kodaka, M., "The mammalian Hippo pathway : regulation and function of YAP1 and TAZ", Cell Mol. Life Sci, 72, pp.285~306 (2015)
- Yuan, Y., "YAP1", TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity, 2020, pp.11, 1472~
- Chen, X., "Role of Hippo-YAP1", TAZ pathway and its crosstalk in cardiac biology, 2020, pp.16, 2454~2463
- Chen, X., "Molecular mechanism of hippo-YAP1", TAZ pathway in heart development, disease, and regeneration, 2020, pp.11, 389~
- Lee, M., "Hippo-yap signaling in ocular development and disease", Dev. Dyn, 247, pp.794~806 (2018)
- Dieffenbach, P. B., "Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP", TAZ-mediated repression of cyclooxygenase-2, 2017, pp.313, L628~L647
- Xie, C., "Yap1 protein regulates vascular smooth muscle cell phenotypic switch by interaction with myocardin", J. Biol. Chem, 287, pp.14598~14605 (2012)
- Zhang, Q., "Activation of AMPK inhibits Galectin-3-induced pulmonary artery smooth muscle cells proliferation by upregulating hippo signaling effector YAP", Mol. Cell Biochem, 476, pp.3037~3049 (2021)
- Shen, H., "MDM2-mediated ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension", Circulation, 142, pp.1190~1204 (2020)
- Jia, D., "Niacin attenuates pulmonary hypertension through H-PGDS in macrophages", Circ. Res, 127, pp.1323~1336 (2020)
- Zhou, X. L., "NSD2 silencing alleviates pulmonary arterial hypertension by inhibiting trehalose metabolism and autophagy", Clin. Sci. (Lond. ), 133, pp.1085~1096 (2019)
- Wang, L. E., "Expression of hypoxia-inducible factor-1α, endothelin-1 and adrenomedullin in newborn rats with hypoxia-induced pulmonary hypertension", Exp. Ther. Med, 8, pp.335~339 (2014)
- Cao, X., "The IRE1α-XBP1 pathway function in hypoxiainduced pulmonary vascular remodeling, is upregulated by quercetin, inhibits apoptosis and partially reverses the effect of quercetin in PASMCs", Am. J. Transl. Res, 11, pp.641~654 (2019)
- Torre, S., "USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation", Nat. Immunol, 18, pp.54~63 (2017)
- Lu, Y., "ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection", Nat. Microbiol, 4, pp.2331~2346 (2019)
- Mitra, A., "Significance of pulmonary hypertension in hypertrophic cardiomyopathy", Curr. Probl. Cardiol, 45, pp.100398~ (2020)
- Dini, F. L., "Doppler-derived mitral and pulmonary venous flow variables are predictors of pulmonary hypertension in dilated cardiomyopathy", Echocardiography, 19, pp.457~465 (2002)
- Bikou, O., "Induction and characterization of pulmonary hypertension in mice using the hypoxia", SU5416 model, 2020, pp.160, e59252~
- Aliotta, J. M., "Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice", Cardiovasc. Res, 110, pp.319~330 (2016)
- Chen, Y. J., "Upregulation of IRF9 contributes to pulmonary artery smooth muscle cell proliferation during pulmonary arterial hypertension", Front. Pharmacol, 12, pp.773235~ (2021)
- Wang, G., "Up-regulated lipocalin-2 in pulmonary hypertension involving in pulmonary artery SMC resistance to apoptosis", Int. J. Biol. Sci, 10, pp.798~806 (2014)
- Zhang, H., "Bone morphogenetic protein-7 inhibits endothelial-mesenchymal transition in pulmonary artery endothelial cell under hypoxia", J. Cell Physiol, 233, pp.4077~4090 (2018)
- Xu, Y., "Stox1 induced the proliferation and cell cycle arrest in pulmonary artery smooth muscle cells via AKT signaling pathway", Vasc. Pharmacol, 120, pp.106568~ (2019)
- Wilson, J. L., "Participation of PLK1 and FOXM1 in the hyperplastic proliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension", PloS One, 14, pp.e0221728~ (2019)
- Maehama, T., "The role of Hippo-YAP signaling in squamous cell carcinomas", Cancer Sci, 112, pp.51~60 (2021)
- Giraud, J., "Verteporfin targeting YAP1", TAZ-TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells, 2020, pp.146, 2255~2267
- Eder, N., "YAP1", TAZ drives ependymoma-like tumour formation in mice, 2020, pp.11, 2380~
- Hou, N., "Activation of Yap1", Taz signaling in ischemic heart disease and dilated cardiomyopathy, 2017, pp.103, 267~275
- Liu, C. Y., "The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF{beta}-TrCP E3 ligase", J. Biol. Chem, 285, pp.37159~37169 (2010)
- Zhu, H., "USP10 promotes proliferation of hepatocellular carcinoma by deubiquitinating and stabilizing YAP", TAZ, 2020, pp.80, 2204~
- Wang, J., "S1P induces proliferation of pulmonary artery smooth muscle cells by promoting YAP-induced Notch3 expression and activation", J. Biol. Chem, 296, pp.100599~ (2021)
- Kim, J., "USP15 deubiquitinates TUT1 associated with RNA metabolism and maintains cerebellar homeostasis", Mol. Cell Biol, 40, pp.e00098-20~ (2020)
- Zhao, Y., "USP15 enhances re-epithelialization through deubiquitinating EIF4A1 during cutaneous wound repair", Front. Cell Dev. Biol, 8, pp.529~ (2020)
- Walczak, H., "Generation and physiological roles of linear ubiquitin chains", BMC Biol, 10, pp.23~ (2012)