The Ubiquitin-Like SUMO System and Heart Function

Mendler, Luca; Braun, Thomas; Müller, Stefan

doi:10.1161/circresaha.115.307730

Cited by 87 publications

(104 citation statements)

References 164 publications

(226 reference statements)

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“…The SUMO pathway has been shown to be active in slow processes in the heart, including cardiac development, regulation of metabolism, and disease progression (36). 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).…”

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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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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“…Sumo3 functions in post-translational sumoylation of proteins regulating immunoglobulin production by B-cells [191] and cytokine production in T-cells [192]. In addition, tight regulation of Sumo proteins has been shown to be critical for cardiac development, cardiac metabolism and cardiac contractility [193]. In another gene methylation screen in Down syndrome, RUNX1 was identified [194].…”

Section: Genetic Influence Of Trisomy 21 On Immune System Disturbancementioning

confidence: 99%

What people with Down Syndrome can teach us about cardiopulmonary disease

Colvin

Yeager

2017

Eur Respir Rev

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Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with cognitive impairment, congenital malformations ( particularly cardiovascular) and dysmorphic features. Immune disturbances in Down syndrome account for an enormous disease burden ranging from quality-of-life issues (autoimmune alopecia) to more serious health issues (autoimmune thyroiditis) and life-threatening issues (leukaemia, respiratory tract infections and pulmonary hypertension). Cardiovascular and pulmonary diseases account for ∼75% of the mortality seen in persons with Down syndrome. This review summarises the cardiovascular, respiratory and immune challenges faced by individuals with Down syndrome, and the genetic underpinnings of their pathobiology. We strongly advocate increased comparative studies of cardiopulmonary disease in persons with and without Down syndrome, as we believe these will lead to new strategies to prevent and treat diseases affecting millions of people worldwide.

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“…However, constitutively increased sumoylation has rather negative effects and correlates with resistance to cancer treatments, increased tumor metastasis and relapse (20)(21)(22)(23)(24). Also, several other diseases, like neurological disorders, diabetes and heart failure, were connected to defects in the SUMO system (25)(26)(27)(28). Together, these findings point to an important role of sumoylation in maintaining cell homeostasis and it is of key importance to understand its substrate specificity and regulation.…”

Section: Introductionmentioning

confidence: 99%

SUMO conjugation – a mechanistic view

Pichler

Fatouros

Lee

et al. 2017

Biomolecular Concepts

211

223

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Abstract:The regulation of protein fate by modification with the small ubiquitin-related modifier (SUMO) plays an essential and crucial role in most cellular pathways. Sumoylation is highly dynamic due to the opposing activities of SUMO conjugation and SUMO deconjugation. SUMO conjugation is performed by the hierarchical action of E1, E2 and E3 enzymes, while its deconjugation involves SUMO-specific proteases. In this review, we summarize and compare the mechanistic principles of how SUMO gets conjugated to its substrate. We focus on the interplay of the E1, E2 and E3 enzymes and discuss how specificity could be achieved given the limited number of conjugating enzymes and the thousands of substrates.

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The Ubiquitin-Like SUMO System and Heart Function

Abstract: SUMOylation is a transient and reversible PTM in which SUMO proteins are conjugated to lysine residues of target proteins. 8,9 In human, 4 SUMO isoforms (SUMO1, 2, 3, and 4) have been identified to date, which share a common

Cited by 87 publications

References 164 publications

SUMOylation determines the voltage required to activate cardiac I _Ks channels

SUMOylation determines the voltage required to activate cardiac I _Ks channels

What people with Down Syndrome can teach us about cardiopulmonary disease

SUMO conjugation – a mechanistic view

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The Ubiquitin-Like SUMO System and Heart Function

Abstract: SUMOylation is a transient and reversible PTM in which SUMO proteins are conjugated to lysine residues of target proteins. 8,9 In human, 4 SUMO isoforms (SUMO1, 2, 3, and 4) have been identified to date, which share a common

Cited by 87 publications

References 164 publications

SUMOylation determines the voltage required to activate cardiac I Ks channels

SUMOylation determines the voltage required to activate cardiac I Ks channels

What people with Down Syndrome can teach us about cardiopulmonary disease

SUMO conjugation – a mechanistic view

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SUMOylation determines the voltage required to activate cardiac I _Ks channels

SUMOylation determines the voltage required to activate cardiac I _Ks channels