E3 ligase CHIP and Hsc70 regulate Kv1.5 protein expression and function in mammalian cells

Li, Peili; Kurata, Yasutaka; Maharani, Nani; Mahati, Endang; Higaki, Kazutaka; Hasegawa, Akira; Shirayoshi, Yasuaki; Yoshïda, Akio; Kondo, Tatehito; Kurozawa, Youichi; Yamamoto, Kazuhide; Ninomiya, Haruaki; Hisatome, Ichiro

doi:10.1016/j.yjmcc.2015.07.018

Cited by 21 publications

(20 citation statements)

References 27 publications

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“…The expression of Kv1.5 channel proteins on the plasma membrane depends on the balance between protein biosynthesis and degradation. 25,26 Delayed degradation through the ubiquitin-proteasome system may be involved in the uric acid-induced increase of Kv1.5 expression as described in the present study. We did not observe any significant effect of uric acid on mRNA of Kv1.5, suggesting post-translational modifications of Kv1.5 proteins facilitated by uric acid.…”

Section: Discussionsupporting

confidence: 62%

“…We have reported that a proteasome inhibitor prolongs Kv1.5 protein's half-life and increases both Kv1.5 protein expression and channel currents. 25,26 Ubiquitination of Kv1.5 proteins was increased by overexpression of carboxylterminus heat shock cognate 70-interacting protein (CHIP), an E3 ubiquitin ligase, and co-expression of CHIP and heat shock cognate 70 (Hsc70) enhanced Kv1.5 protein degradation. 25 HSF1 is activated by oxidative stress; 6 activation of HSF1 by oxidative stress induces the enhanced expression of heat shock proteins.…”

Section: Disclosuresmentioning

confidence: 99%

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Uric Acid-Induced Enhancements of Kv1.5 Protein Expression and Channel Activity via the Akt-HSF1-Hsp70 Pathway in HL-1 Atrial Myocytes

Taufiq

Maharani

et al. 2019

Circ J

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increase the protein level of voltage-gated potassium channel subfamily 1 number 5 (Kv1.5) by increasing the NADPHdependent oxidative stress level in HL-1 mouse atrial myocytes. 8 Uric acid may lead to inductions of arrhythmias including AF and resultant increases in cardiovascular mortality via the enhancement of Kv1.5 expression. However, precise molecular mechanisms underlying the uric U ric acid is the end product of purine catabolism in a human body. 1 Many reports indicated a positive correlation between serum uric acid concentration and morbidity or mortality of cardiovascular diseases including atrial fibrillation (AF). 2-5 It is well known that increases in potassium channel currents shorten the atrial refractory period to facilitate the development of re-entry circuits, leading to AF. Escalation of cardiovascular morbidity and mortality has been attributed to oxidative stress. 6,7 Our previous study indicated that uric acid could Editorial p 705

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Section: Discussionsupporting

confidence: 62%

Section: Disclosuresmentioning

confidence: 99%

Uric Acid-Induced Enhancements of Kv1.5 Protein Expression and Channel Activity via the Akt-HSF1-Hsp70 Pathway in HL-1 Atrial Myocytes

Taufiq

Maharani

et al. 2019

Circ J

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“…However, Hsp70-bound proteins associating with CHIP are targeted to endoplasmic reticulum-associated degradation via the ubiquitin proteasome system. [32][33][34] The association of AQP2, CHIP, and Hsp70 in a protein complex plus the greater abundance of AQP2 in mpkCCD cells with stable knockdown of CHIP or in CHIP gene-modified mice suggest that AQP2 is subject to similar quality control (QC) mechanisms. Therefore, in the absence of CHIP, there is a shift in balance toward AQP2 protein folding rather than degradation.…”

Section: Discussionmentioning

confidence: 99%

CHIP Regulates Aquaporin-2 Quality Control and Body Water Homeostasis

Moeller

Stevens

et al. 2017

JASN

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The importance of the kidney distal convoluted tubule (DCT) and cortical collecting duct (CCD) is highlighted by various water and electrolyte disorders that arise when the unique transport properties of these segments are disturbed. Despite this critical role, little is known about which proteins have a regulatory role in these cells and how these cells can be regulated by individual physiologic stimuli. By combining proteomics, bioinformatics, and cell biology approaches, we found that the E3 ubiquitin ligase CHIP is highly expressed throughout the collecting duct; is modulated in abundance by vasopressin; interacts with aquaporin-2 (AQP2), Hsp70, and Hsc70; and can directly ubiquitylate the water channel AQP2 shRNA knockdown of CHIP in CCD cells increased AQP2 protein and reduced AQP2 ubiquitylation, resulting in greater levels of AQP2 and phosphorylated AQP2. CHIP knockdown increased the plasma membrane abundance of AQP2 in these cells. Compared with wild-type controls, CHIP knockout mice or novel CRISPR/Cas9 mice without CHIP E3 ligase activity had greater AQP2 abundance and altered renal water handling, with decreased water intake and urine volume, alongside higher urine osmolality. We did not observe significant changes in other water- or sodium-transporting proteins in the gene-modified mice. In summary, these results suggest that CHIP regulates AQP2 and subsequently, renal water handling.

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“…There is surprisingly little known about the ERAD of these channels. CHIP and Hsc70/Hsp70 have been implicated in the degradation of cardiac KCNA5/Kv1.5 channels and KCNQ4/Kv7.4 in auditory sensory neurons (55,56). Whether TRC8 contributes to the degradation of these and related channels remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

Hantouche

Williamson

Valinsky

et al. 2017

Journal of Biological Chemistry

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Edited by George N. DeMartinoCardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go-related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity. Dissociation of hERG complexes containing Hsp70 and the E3 ubiquitin ligase CHIP requires the interaction of Bag1 with Hsp70, but this does not involve the Bag1 ubiquitin-like domain. The interaction with Bag1 then shifts hERG degradation to the membrane-anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening. TRC8 interacts through the transmembrane region with hERG and decreases hERG functional expression. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, but pharmacological stabilization of the mutant structure prevents degradation. Our results identify TRC8 as a previously unknown Hsp70-independent quality control E3 ligase for hERG.

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E3 ligase CHIP and Hsc70 regulate Kv1.5 protein expression and function in mammalian cells

Cited by 21 publications

References 27 publications

Uric Acid-Induced Enhancements of Kv1.5 Protein Expression and Channel Activity via the Akt-HSF1-Hsp70 Pathway in HL-1 Atrial Myocytes

Uric Acid-Induced Enhancements of Kv1.5 Protein Expression and Channel Activity via the Akt-HSF1-Hsp70 Pathway in HL-1 Atrial Myocytes

CHIP Regulates Aquaporin-2 Quality Control and Body Water Homeostasis

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

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