The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor

Bi, Hai-Lian; Zhang, Xiaoli; Zhang, Yun-Long; Xie, Xin; Xia, Yunlong; Du, Jie; Li, Huihua

doi:10.1126/sciadv.aax4826

Cited by 63 publications

(69 citation statements)

References 46 publications

(66 reference statements)

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“…Furthermore, the UPS plays a key role in maintaining protein homeostasis and cardiac function, and UCHL1 has been shown to play a key role in this regulation. Knockdown of UCHL1 in cardiomyocytes and mouse hearts rescued cardiac hypertrophy induced by agonist or pressure overload, and overexpression resulted in the opposite effect [ 28 ]. We have not carried out functional studies of mutated UCHL1 protein (p.Gly210del).…”

Section: Discussionmentioning

confidence: 99%

Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion

et al. 2020

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Background Behr syndrome is a clinically distinct, but genetically heterogeneous disorder characterized by optic atrophy, progressive spastic paraparesis, and motor neuropathy often associated with ataxia. The molecular diagnosis is based on gene panel testing or whole-exome/genome sequencing. Methods Here, we report the clinical presentation of two siblings with a novel genetic form of Behr syndrome. We performed whole-exome sequencing in the two patients and their mother. Results Both patients had a childhood-onset, slowly progressive disease resembling Behr syndrome, starting with visual impairment, followed by progressive spasticity, weakness, and atrophy of the lower legs and ataxia. They also developed scoliosis, leading to respiratory problems. In their late 30’s, both siblings developed a hypertrophic cardiomyopathy and died of sudden cardiac death at age 43 and 40, respectively. Whole-exome sequencing identified the novel homozygous c.627_629del; p.(Gly210del) deletion in UCHL1. Conclusions The presentation of our patients raises the possibility that hypertrophic cardiomyopathy may be an additional feature of the clinical syndrome associated with UCHL1 mutations, and highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations.

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Section: Discussionmentioning

confidence: 99%

Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion

et al. 2020

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“…Microgram quantities of biotin‐labeled complementary RNA were fractionated and hybridized to Affymetrix GeneChip. The microarray data were analyzed as previously described (Bi et al, 2020; Dang et al, 2015; D. Yang et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

Deubiquitinase USP18 regulates reactive astrogliosis by stabilizing SOX9

Liu

Zhou

et al. 2021

Glia

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Reactive astrogliosis is a pathological feature of spinal cord injury (SCI). The ubiquitin‐proteasome system plays a crucial role in maintaining protein homeostasis and has been widely studied in neuroscience. Little, however, is known about the underlying function of deubiquitinating enzymes in reactive astrogliosis following SCI. Here, we found that ubiquitin‐specific protease 18 (USP18) was significantly upregulated in astrocytes following scratch injury, and in the injured spinal cord in mice. Knockdown of USP18 in vitro and conditional knockout of USP18 in astrocytes (USP18 CKO) in vivo significantly attenuated reactive astrogliosis. In mice, this led to widespread inflammation and poor functional recovery following SCI. In contrast, overexpression of USP18 in mice injected with adeno‐associated virus (AAV)‐USP18 had beneficial effects following SCI. We showed that USP18 binds, deubiquitinates, and thus, stabilizes SRY‐box transcription factor 9 (SOX9), thereby regulating reactive astrogliosis. We also showed that the Hedgehog (Hh) signaling pathway induces expression of USP18 through Gli2‐mediated transcriptional activation after SCI. Administration of the Hh pathway activator SAG significantly increased reactive astrogliosis, reduced lesion area and promoted functional recovery in mice following SCI. Our results demonstrate that USP18 positively regulates reactive astrogliosis by stabilizing SOX9 and identify USP18 as a promising target for the treatment of SCI.

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“…By suppressing intrinsic apoptosis, UCHL1 ameliorates type 2 diabetes and Alzheimer's disease. Conversely, UCHL1 promotes high-glucose-induced extrinsic apoptosis and necroptosis, which promote diabetic nephropathy (Figure 4a) [55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70]. In malignant diseases, DUBs can aggravate or ameliorate cancers, depending on their downstream RCD.…”

Section: Dubs Regulating Diverse Rcdmentioning

confidence: 99%

“…In a cardiac hypertrophy model (both in vitro and in vivo), UCHL1 expression was upregulated. Downregulation of UCHL1 expression decreases apoptosis and EGFR signaling and suppresses heart remodeling after the onset of cardiac hypertrophy [ 56 ]. A recent study demonstrated that podocytes undergo apoptosis and necroptosis during diabetic nephropathy.…”

Section: Dubs Regulating Diverse Rcdmentioning

confidence: 99%

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

Lee

Kim

Hwang

et al. 2021

IJMS

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The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators.

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The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor

Cited by 63 publications

References 46 publications

Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion

Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion

Deubiquitinase USP18 regulates reactive astrogliosis by stabilizing SOX9

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

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