KCNE gene expression is dependent on the proliferation and mode of activation of leukocytes

Solé, Laura; Vallejo-Gracia, Albert; Roig, Sara R.; Serrano-Albarrás, Antonio; Marruecos, Laura; Manils, Joan; Gómez, Diana; Soler, Concepció; Felipe, Antônio

doi:10.4161/chan.23258

Cited by 11 publications

(14 citation statements)

References 40 publications

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“…Therefore, the abundance of KCNE4 could exert important functional consequences on the cell. Thus, KCNE4 was overexpressed in Jurkat T cells, which have a limited amount of KCNE4 (6,20). KCNE4-CFPpositive cells (Fig.…”

Section: Kcne4 Regulates Kv13 In Hek-293 and Jurkat T Cellsmentioning

confidence: 87%

“…The regulation of Kv1.3 by KCNE4 depends on the amount of KCNE4, and both proteins are tightly regulated in leukocytes (6,7). Therefore, the abundance of KCNE4 could exert important functional consequences on the cell.…”

Section: Kcne4 Regulates Kv13 In Hek-293 and Jurkat T Cellsmentioning

confidence: 99%

“…The potassium voltage-gated channel subfamily E (KCNE) family is composed of 5 auxiliary subunits (KCNE1-5), which are small, singlemembrane-spanning proteins that modulate a wide range of potassium channels (5). KCNEs have a wide tissue distribution, and their expression is tightly regulated in the immune system, highlighting the importance of this family in leukocytes (6). KCNE4, the most divergent member of the KCNE family, has dominant negative effects on numerous K + channels, such as Kv7.1, 1.1, 4.2, and KCa1.1 (5).…”

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The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3

et al. 2019

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The voltage‐dependent potassium (Kv) channel Kv1.3 regulates leukocyte proliferation, activation, and apoptosis, and altered expression of this channel is linked to autoimmune diseases. Thus, the fine‐tuning of Kv1.3 function is crucial for the immune system response. The Kv1.3 accessory protein, potassium voltage‐gated channel subfamily E (KCNE) subunit 4, acts as a dominant negative regulatory subunit to both enhance inactivation and induce intracellular retention of Kv1.3. Mutations in KCNE4 also cause immune system dysfunction. Although the formation of Kv1.3‐KCNE4 complexes has profound consequences for leukocyte physiology, the molecular determinants involved in the Kv1.3‐KCNE4 association are unknown. We now show that KCNE4 associates with Kv1.3 via a tetraleucine motif situated within the carboxy‐terminal domain of this accessory protein. This motif would function as an interaction platform, in which Kv1.3 and Ca2+/calmodulin compete for the KCNE4 interaction. Finally, we propose a structural model of the Kv1.3‐KCNE4 complex. Our experimental data and the in silico structure suggest that the KCNE4 interaction hides a forward‐trafficking motif within Kv1.3 in addition to adding a strong endoplasmic reticulum retention signature to the Kv1.3‐KCNE4 complex. Thus, the oligomeric composition of the Kv1.3 channelosome fine‐tunes the precise balance between anterograde and intracellular retention elements that control the cell surface expression of Kv1.3 and immune system physiology.—Sole, L., Roig, S. R., Sastre, D., Vallejo‐Gracia, A., Serrano‐Albarrás, A., Ferrer‐Montiel, A., Fernández‐Ballester, G., Tamkun, M. M., Felipe, A. The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3. FASEB J. 33, 8263–8279 (2019). http://www.fasebj.org

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Section: Kcne4 Regulates Kv13 In Hek-293 and Jurkat T Cellsmentioning

confidence: 87%

Section: Kcne4 Regulates Kv13 In Hek-293 and Jurkat T Cellsmentioning

confidence: 99%

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confidence: 99%

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The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3

et al. 2019

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“…KCNE4 is a regulatory subunit that modulates the cell surface abundance and the spatial localization of Kv1.3 channels. Both proteins are present in leukocytes and form heterooligomeric channels (Sole and Felipe, 2010;Sole et al, 2009Sole et al, , 2013. In the present work, we analyzed the molecular determinants in Kv1.3 that participate in the Kv1.3-KCNE4 interaction.…”

Section: Discussionmentioning

confidence: 99%

The C-terminal domain of Kv1.3 regulates functional interactions with the KCNE4 subunit

Solé

Roig

Vallejo-Gracia

et al. 2016

Journal of Cell Science

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The voltage-dependent K channel Kv1.3 (also known as KCNA3), which plays crucial roles in leukocytes, physically interacts with KCNE4. This interaction inhibits the K currents because the channel is retained within intracellular compartments. Thus, KCNE subunits are regulators of K channels in the immune system. Although the canonical interactions of KCNE subunits with Kv7 channels are under intensive investigation, the molecular determinants governing the important Kv1.3- KCNE4 association in the immune system are unknown. Our results suggest that the tertiary structure of the C-terminal domain of Kv1.3 is necessary and sufficient for such an interaction. However, this element is apparently not involved in modulating Kv1.3 gating. Furthermore, the KCNE4-dependent intracellular retention of the channel, which negatively affects the activity of Kv1.3, is mediated by two independent and additive mechanisms. First, KCNE4 masks the YMVIEE signature at the C-terminus of Kv1.3, which is crucial for the surface targeting of the channel. Second, we identify a potent endoplasmic reticulum retention motif in KCNE4 that further limits cell surface expression. Our results define specific molecular determinants that play crucial roles in the physiological function of Kv1.3 in leukocytes.

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“…The other outstanding question remaining is why Kcne3 deletion causes the adrenal infiltration: which tissue is defective? KCNE3 is expressed in various blood cell lineages, but its role in these cells is not known (21) and certainly also warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Kcne3 deletion initiates extracardiac arrhythmogenesis in mice

Crump

Anand

et al. 2013

FASEB j.

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Mutations in the human KCNE3 potassium channel ancillary subunit gene are associated with life-threatening ventricular arrhythmias. Most genes underlying inherited cardiac arrhythmias, including KCNE3, are not exclusively expressed in the heart, suggesting potentially complex disease etiologies. Here we investigated mechanisms of KCNE3-linked arrhythmogenesis in Kcne3(-/-) mice using real-time qPCR, echo- and electrocardiography, ventricular myocyte patch-clamp, coronary artery ligation/reperfusion, blood analysis, cardiac synaptosome exocytosis, microarray and pathway analysis, and multitissue histology. Kcne3 transcript was undetectable in adult mouse atria, ventricles, and adrenal glands, but Kcne3(-/-) mice exhibited 2.3-fold elevated serum aldosterone (P=0.003) and differentially expressed gene networks consistent with an adrenal-targeted autoimmune response. Furthermore, 8/8 Kcne3(-/-) mice vs. 0/8 Kcne3(+/+) mice exhibited an activated-lymphocyte adrenal infiltration (P=0.0002). Kcne3 deletion also caused aldosterone-dependent ventricular repolarization delay (19.6% mean QTc prolongation in females; P<0.05) and aldosterone-dependent predisposition to postischemia arrhythmogenesis. Thus, 5/11 Kcne3(-/-) mice vs. 0/10 Kcne3(+/+) mice exhibited sustained ventricular tachycardia during reperfusion (P<0.05). Kcne3 deletion is therefore arrhythmogenic by a novel mechanism in which secondary hyperaldosteronism, associated with an adrenal-specific lymphocyte infiltration, impairs ventricular repolarization. The findings highlight the importance of considering extracardiac pathogenesis when investigating arrhythmogenic mechanisms, even in inherited, monogenic channelopathies.

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KCNE gene expression is dependent on the proliferation and mode of activation of leukocytes

Cited by 11 publications

References 40 publications

The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3

The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3

The C-terminal domain of Kv1.3 regulates functional interactions with the KCNE4 subunit

Kcne3 deletion initiates extracardiac arrhythmogenesis in mice

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