Induction of SENP1 in myocardium contributes to abnormities of mitochondria and cardiomyopathy

Cai, Rong; Sun, Haipeng; Liu, Xiaobing; Mei, Wenhan; Qi, Yitao; Xue, Song; Ren, Shuxun; Rabinowitz, Joseph E.; Wang, Yibin; Yeh, Edward T.H.; Cheng, Jinke

doi:10.1016/j.yjmcc.2014.11.014

Cited by 32 publications

(26 citation statements)

References 45 publications

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“…Therefore, the prolonged SENP1 expression observed in human failing hearts might contribute to cardiac dysfunction by altering mitochondrial function. 52 This conclusion is also supported by the finding that forced expression of SENP1 through a virus-based approach induces dilated cardiomyopathy and mitochondrial abnormalities in adult mice 52 (Table). Similar deleterious effects of enhanced SUMO deconjugation in adult heart were also observed after forced expression of SENP2 or SENP5 in the heart, leading to cardiomyopathies and cardiac dysfunction 54,55 (Table).…”

Section: Cardiac Stress Adaptationmentioning

confidence: 82%

“…52 The calcineurin-NFAT3 (nuclear factor of activated T-cells-3) pathway, which is activated during cardiac hypertrophy, induces expression of SENP1. This might be a compensatory effect in the initial phase of hypertrophy, limiting the glycolytic metabolic switch in dysfunctional heart, because SENP1 enhances cardiac PGC-1α expression and subsequent mitochondrial gene activation.…”

Section: Cardiac Stress Adaptationmentioning

confidence: 99%

“…91 Enhanced deSUMOylation by transgenic overexpression of SENP1 in the heart causes activation of PGC-1α and induces cardiomyopathy. 52 However, at present, it is not clear whether the increased activity of PGC-1α solely relies on deSUMOylation of PGC-1α by SENP1 52 or whether other regulatory events participate in this phenomenon. In fact, SENP1 also deSUMOylates MEF2C, a member of the MADS-box transcription factors, which controls expression of PGC-1α in the heart.…”

mentioning

confidence: 99%

“…In fact, SENP1 also deSUMOylates MEF2C, a member of the MADS-box transcription factors, which controls expression of PGC-1α in the heart. 52 Because SUMOylation inhibits the activity of MEF2 factors, [92][93][94] SENP1-mediated activation of MEF2C will increase PGC-1α transcription. Future experiments might disclose the relative input of each pathway for SENP1-mediated activation of PGC-1α in transgenic mouse hearts.…”

mentioning

confidence: 99%

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The Ubiquitin-Like SUMO System and Heart Function

Mendler

Braun

Müller

2016

Circulation Research

101

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Section: Cardiac Stress Adaptationmentioning

confidence: 82%

Section: Cardiac Stress Adaptationmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Ubiquitin-Like SUMO System and Heart Function

Mendler

Braun

Müller

2016

Circulation Research

101

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“…Thus, heart-specific constitutive overexpression of SENP2 in mice has been associated with major congenital defects in both the atria and ventricles of the heart (37). Whereas, chronic viral overexpression of SUMO1 has been reported to have a positive role in treating heart failure, improving cardiomyocyte intracellular calcium homeostasis via effects on SERCA2A calcium pump activity in both a pressure overload heart failure model in mice (38) and an ischemia heart failure model in swine (39), inducible overexpression of SENP1 in mice is reported to produce mitochondrial dysfunction in ventricular myocytes and attributes resembling heart failure in humans (40). That two manipulations that increase SUMOylation appear to have opposite effects on the heart is likely to reflect the multiplicity of SUMO pathway targets, stimulus-dependent changes in SUMOylation/deSUMOylation, chronic and acute changes over time, and our nascent understanding of the SUMO pathway.…”

Section: Discussionmentioning

confidence: 99%

SUMOylation determines the voltage required to activate cardiac I _Ks channels

Xiong

Dai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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I Ks channels open in response to depolarization of the membrane voltage during the cardiac action potential, passing potassium ions outward to repolarize ventricular myocytes and end each beat. Here, we show that the voltage required to activate I Ks channels depends on their covalent modification by small ubiquitin-like modifier (SUMO) proteins. I Ks channels are comprised of four KCNQ1 poreforming subunits, two KCNE1 accessory subunits, and up to four SUMOs, one on Lys 424 of each KCNQ1 subunit. Each SUMO shifts the half-maximal activation voltage (V 1/2 ) of I Ks ∼ +8 mV, producing a maximal +34-mV shift in neonatal mouse cardiac myocytes or Chinese hamster ovary (CHO) cells expressing the mouse or human subunits. Unexpectedly, channels formed without KCNE1 carry at most two SUMOs despite having four available KCNQ1-Lys 424 sites. SUMOylation of KCNQ1 is KCNE1 dependent and determines the native attributes of cardiac I Ks in vivo.C ardiac I Ks channels pass the slow component of the delayed rectifier potassium current that is necessary to produce normal heart rate and rhythm. Thus, I Ks varies in magnitude and timing subject to neuronal and hormonal influences (1). Abnormal changes in I Ks function, due to inherited mutations in KCNQ1 or KCNE1, or suppression of the current by medications, can produce long QT syndrome (LQTS) and life-threatening cardiac arrhythmias (2). KCNQ1 (also called K V 7.1 and previously K V LQT) is a classical voltage-gated potassium α-subunit with six transmembrane segments and a single pore-forming P loop. Human KCNQ1 has variants up to 676 residues in length, whereas KCNE1 (minK) has just 129 residues and a single transmembrane span (Fig. 1A). Despite its small size, KCNE1 is essential to the operation of I Ks . Compared with channels formed by KCNQ1 subunits alone, KCNE1 produces a right shift in the half-maximal voltage required to activate the channel (V 1/2 ), slows the kinetics of activation and deactivation, increases the channel unitary conductance, alters the ion selectivity of the conduction pore and, modifies its pharmacology (3-8). KCNE1 also endows I Ks channel with a high affinity for PIP 2 (9) and allows responsiveness to PKA-mediated phosphorylation following β-adrenergic stimulation (10). Here, we demonstrate that the V 1/2 inherent to native cardiac I Ks channels results from, and is modified by, KCNE1-dependent SUMOylation of KCNQ1.SUMOylation is the enzyme-mediated linkage of one of three SUMO isoforms to the e-amino group of specific Lys residues on a target protein (11). Present in all eukaryotic cells, the pathway was recognized to regulate the activity of nuclear transcription factors when we discovered it resident at the plasma membrane (12, 13) and to regulate the excitability of cerebellar granule neurons via SUMOylation of K2P1 and Na V 1.2 (14, 15), and of hippocampal neurons via modification of K V 2.1 (16).This study was inspired by the work of Qi et al. (17), who describe partial deficiency of the deSUMOylating enzyme SENP2 in mice, showing it to pro...

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SUMO‐specific proteases: SENPs in oxidative stress‐related signaling and diseases

Jiao,

Zhang,

Yang

2024

BioFactors

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Oxidative stress is employed to depict a series of responses detrimental to normal cellular functions resulting from an imbalance between intracellular oxidants, mainly reactive oxygen species and antioxidant defenses. Oxidative stress often contributes to the development of various diseases, including cancer, cardiovascular diseases, and neurodegenerative diseases. In this process, the relationship between small ubiquitin‐like modifier (SUMO) and oxidative stress has garnered significant attention, with its posttranslational modification (PTM) frequently serving as a marker of oxidative stress status. Sentrin/SUMO‐specific proteases (SENPs), affected by alternative splicing, PTMs such as phosphorylation and ubiquitination, and various protein interactions, are crucial molecules in the SUMO process. The human SENP family has six members (SENP1–3, SENP5–7), which are classified into two categories based on sequence similarity, substrate specificity, and subcellular location. They have two core functions in the human body: first, by cleaving the precursor SUMO and exposing the C‐terminal glycine, they initiate the SUMO process; second, they can specifically recognize and dissociate SUMO proteins bound to substrates, a process known as deSUMOylation. However, the connection between deSUMOylation and oxidative stress remains a relatively unexplored area despite their strong association with oxidative diseases such as cancer and cardiovascular disease. This article aims to illustrate the significant contribution of SENPs to the oxidative stress pathway through deSUMOylation by reviewing their structure and classification, their roles in oxidative stress, and the changes in their expression and activity in several typical oxidative stress‐related diseases.

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Induction of SENP1 in myocardium contributes to abnormities of mitochondria and cardiomyopathy

Cited by 32 publications

References 45 publications

The Ubiquitin-Like SUMO System and Heart Function

The Ubiquitin-Like SUMO System and Heart Function

SUMOylation determines the voltage required to activate cardiac I _Ks channels

SUMO‐specific proteases: SENPs in oxidative stress‐related signaling and diseases

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Induction of SENP1 in myocardium contributes to abnormities of mitochondria and cardiomyopathy

Cited by 32 publications

References 45 publications

The Ubiquitin-Like SUMO System and Heart Function

The Ubiquitin-Like SUMO System and Heart Function

SUMOylation determines the voltage required to activate cardiac I Ks channels

SUMO‐specific proteases: SENPs in oxidative stress‐related signaling and diseases

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Product

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About

SUMOylation determines the voltage required to activate cardiac I _Ks channels