Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Abstract

Abstract-Dysregulation of the ubiquitin proteasome system components ubiquitin ligases and proteasome plays an important role in the pathogenesis of cardiac hypertrophy. However, little is known about the role of another ubiquitin proteasome system component, the deubiquitinating enzymes, in cardiac hypertrophy. Here, we revealed a crucial role of ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme prominently expressed in the heart, in attenuating pathological cardiac hypertrophy and dysfunction. USP4 levels were consistently decreased in human failing hearts and in murine hypertrophied hearts. Adenovirus-mediated gain-and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II. To corroborate the role of USP4 in vivo, we generated USP4 global knockout mice and mice with cardiac-specific overexpression of USP4. Consistent with the in vitro study, USP4 depletion exacerbated the hypertrophic phenotype and cardiac dysfunction in mice subjected to pressure overload, whereas USP4 transgenic mice presented ameliorated pathological cardiac hypertrophy compared with their control littermates. Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo. These findings provide the first evidence for the involvement of USP4 in cardiac hypertrophy, and shed light on the therapeutic potential of targeting USP4 in the treatment of cardiac hypertrophy. promotes ionizing radiation-induced cell apoptosis by specifically reducing p53 expression. 13 Of note, USP4 is a putative proto-oncogene, which promotes epithelial to mesenchymal transition and breast cancer cell migration. 18 Interestingly, mounting evidence supports pivotal roles of proto-oncogenes in modulating cardiac hypertrophy, 19,20 indicating a potential involvement of USP4 in cardiac hypertrophy. We therefore posited that USP4, a DUB prominently expressed in the heart, might be a potential signaling regulator implicated in cardiac hypertrophy.In this study, we observed reduced levels of USP4 in hearts from patients with dilated cardiomyopathy and in animal models of cardiac hypertrophy induced by pressure overload. By subjecting USP4 knockout mice and transgenic mice with cardiac-specific USP4 overexpression to aortic banding (AB), we observed that USP4 deficiency aggravated hypertrophic growth and cardiac dysfunction. Conversely, restoration of USP4 level remarkably protected the heart against pathological hypertrophy. Mechanistically, the beneficial effect of USP4 was largely dependent on the blockade of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling. Materials and MethodsThe animal protocol was approved by the Instit...

Ubiquitin‐Specific Protease 4 Is an Endogenous Negative Regulator of Metabolic Dysfunctions in Nonalcoholic Fatty Liver Disease in Mice

“…Pioglitazone failed to significantly improve primary outcomes and led to significant weight gain, and a proportion of recruited NAFLD patients failed to respond to vitamin E, calling for identification of novel therapeutic targets. Here, by using multiple genetically modified mouse lines and different NAFLD models, we provide evidence that USP4, a cardioprotective deubiquitinating enzyme, acted as a negative regulator of obesity‐related HS and glucose metabolism disruption, suggesting that USP4 may represent a target that might exert hepatic and cardiac benefits in the pathogenesis of NAFLD. Of note, because many small molecules targeting deubiquitinating enzymes have been approved or are under testing for clinical applications, the present experimental findings also provided rationale for potential drug repurposing.…”

“…The deubiquitinating enzyme, ubiquitin specific protease 4 (USP4), a unique member of USPs, was first identified as an oncogene cloned from a mouse complementary DNA library and with strong similarity to the human tre oncogene . We previously demonstrated that USP4 was an endogenous cardioprotective enzyme against cardiac remodeling by negatively regulating activity of c‐Jun N‐terminal kinase (JNK), a kinase that pivotally promotes NAFLD . Moreover, USP4 is a key regulator of diverse signaling pathways, such as tumor necrosis factor alpha (TNFα)/tumor necrosis factor receptor, lipopolysaccharide/Toll‐like receptor, and interleukin (IL)‐1β/IL‐1R, thus exerting potent suppressive effect on inflammatory response, which is an important mediator of NAFLD progression .…”

Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling

“…TAK1 is a key kinase that activates downstream p38 and JNK1/2 kinase and plays a pivotal role during cardiac remodeling. [21][22][23]35 Considering that TAK1 is an upstream regulator of p38 and JNK1/2 kinase, we predicted that USP18 may regulate TAK1 activity. Indeed, our results showed that USP18 deficiency enhanced TAK1 activity, whereas USP18 overexpression displayed the opposite response.…”

RNPS1 is modulated by ubiquitin‐specific protease 4

“…SR proteins play a significant role in pre-mRNA splicing because diverse SR proteins including serine/arginine-rich splicing factor 1 (SRSF1), SC35, hTra2a and RNPS1 regulate pre-mRNA splicing by affecting transcription, mRNA export, genome stability, nonsense-mediated decay and translation [12,52]. USP4 affects neuronal apoptosis in the intracerebral hemorrhage pathway [53], which could be correlated with human breast cancer migration and invasion by promoting relaxin/transforming growth factor-b1/ Smad2/matrix metallopeptidase 9 signalling [54], and also modulates the activation of transforming growth factor b-activated kinase 1-(JNK1/2)/p38 signalling in cardiac hypertrophy [55]. USP4 is an attractive DUB involved in a variety of cellular mechanisms.…”

“…Therefore, USP4 is related to different aspects of cancer as an indispensable DUB by regulating cellular signalling. USP4 affects neuronal apoptosis in the intracerebral hemorrhage pathway [53], which could be correlated with human breast cancer migration and invasion by promoting relaxin/transforming growth factor-b1/ Smad2/matrix metallopeptidase 9 signalling [54], and also modulates the activation of transforming growth factor b-activated kinase 1-(JNK1/2)/p38 signalling in cardiac hypertrophy [55]. In addition, it influences bcatenin stabilization to affect metastatic potential [56], modulates the antiviral response by regulating retinoic acid-inducible gene I [57] and correlates with colorectal oncogenesis by regulating phosphatase of regenerating liver-3 [58].…”