Toll‐like receptor 3 controls QT interval on the electrocardiogram by targeting the degradation of Kv4.2/4.3 channels in the endoplasmic reticulum

Abstract

TLRs have been proven to be essential mediators for the early innate immune response. Overactivation of TLR‐mediated immune signaling promotes deterioration of cardiovascular diseases; however, the role of TLRs in the heart under physiologic conditions remains neglected. Here, we show that Tlr3 deficiency induced the endoplasmic reticulum (ER) retention of Kv4.2/4.3 proteins and consequent degradation via the ubiquitin‐proteasome pathway. Knockout of Tlr3 resulted in a prolonged QT interval (the space between the start of the Q wave and the end of the T wave) in mice with no significant signs of inflammation and tissue abnormality in cardiac muscles. Prolongation of action potential duration resulted from the depression of transient outward potassium channel (Ito) currents in Tlr3‐deficient ventricular myocytes mirrored the change in QT interval. Mechanistically, we found that Tlr3 was exclusively localized in the ER of cardiomyocytes where it interacted with Kv4.2/4.3 subunits of Ito channel. Thus, our data indicated that TLR3 directly regulates Ito channel protein dynamics to maintain cardiac repolarization, which may implicate a new molecular surveillance system for cardiac electrophysiological homeostasis.—Gao, X., Gao, S., Guan, Y., Huang, L., Huang, J., Lin, L., Liu, Y., Zhao, H., Huang, B., Yuan, T., Liu, Y., Liang, D., Zhang, Y., Ma, X., Li, L., Li, J., Zhou, D., Shi, D., Xu, L., Chen, Y.‐H. Toll‐like receptor 3 controls QT interval on the electrocardiogram by targeting the degradation of Kv4.2/4.3 channels in the endoplasmic reticulum. FASEB J. 33, 6197–6208 (2019). http://www.fasebj.org

E3 ubiquitin ligase rififylin has yin and yang effects on rabbit cardiac transient outward potassium currents (Ito) and corresponding channel proteins

“…The complexity of ubiquitination outcomes is the result of different types of ubiquitinations, such as monoubiquitination, multimonoubiquitination, homotypic ubiquitination, heterotypic ubiquitination, modified ubiquitination, etc., which lead to different consequences ( 33 ). In addition, there is the Ub-proteasome pathway–mediated Kv4.3 degradation, which apparently does not involve RFFL ( 34 ). There are also other enzymes that affect trafficking of the channel proteins underlying I to , which potentially might also be affected by RFFL ( 23 , 35 ).…”

RNA Signaling in Pulmonary Arterial Hypertension—A Double-Stranded Sword

“…TLR3-deficient mice had prolonged QT intervals, associated with reduced amplitude of current intensity compared to control cells and this was independent of MyD88 and TRIF signaling and unaffected by poly(I:C) stimulation [81]. TLR3 predominantly resided in the endoplasmic reticulum of cardiomyocytes, which express little of the UNC93B1 chaperone protein, and was found to be important for potassium channel synthesis [81]. This work indicates a tissue-specific role in the context of limited endosomal TLR3 trafficking, but whether this is important in other cells or whether TLR3 is involved in the stabilization of other proteins remains unknown.…”

“…A further interesting observation in cardiomyocytes demonstrated that TLR3 regulation of tissue homeostasis may also occur without dsRNA stimulation. Gao et al (2019) revealed the role for TLR3 in the regulation of potassium channels and cardiac electrophysiological homeostasis that was not dependent on downstream immune signals. TLR3-deficient mice had prolonged QT intervals, associated with reduced amplitude of current intensity compared to control cells and this was independent of MyD88 and TRIF signaling and unaffected by poly(I:C) stimulation [81].…”

“…Gao et al (2019) revealed the role for TLR3 in the regulation of potassium channels and cardiac electrophysiological homeostasis that was not dependent on downstream immune signals. TLR3-deficient mice had prolonged QT intervals, associated with reduced amplitude of current intensity compared to control cells and this was independent of MyD88 and TRIF signaling and unaffected by poly(I:C) stimulation [81]. TLR3 predominantly resided in the endoplasmic reticulum of cardiomyocytes, which express little of the UNC93B1 chaperone protein, and was found to be important for potassium channel synthesis [81].…”