Translationally controlled tumor protein interacts with connexin 43 and facilitates intercellular coupling between cardiomyocytes

Yaopeng Hu ¹ Wenqian Cai ² Yuko Hidaka ³ Keizo Hiraishi ¹ Jiehui Cang ¹ Masanari Umemura ⁴ Utako Yokoyama ³ Bjorn C Knollmann ⁵ Yoshihiro Ishikawa ⁴ Takayuki Fujita ^1*

• ¹ Department of Physiology, Fukuoka University School of Medicine, Fukuoka, Japan
• ² Heart Center and Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
• ³ Department of Physiology, Tokyo Medical University, Tokyo, Japan
• ⁴ Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan
• ⁵ Center for Transportation and Operational Resilience, School of Engineering, Vanderbilt University, Nashville, Tennessee, United States

Connexins are gap junction proteins that play pivotal roles in intercellular communication. Connexin 43 (Cx43) is one of the most ubiquitously expressed connexin isoforms in human. Cx43 has been demonstrated to be involved in the pathological process of various diseases, including arrhythmias. Recently, translationally controlled tumor protein (TCTP), a highly conserved anti-apoptotic protein, has been shown to play an important role in protecting against the development of heart failure. However, its role in arrhythmogenesis remains unclear. In this study, we aimed to examine the interaction between TCTP and Cx43 and investigate the roles of TCTP in the formation of Cx43 gap junction channels and gap junctional intercellular communication (GJIC) in cardiomyocytes. Methods and Results: We found that TCTP was predominantly expressed in the intercalated discs of mouse heart tissue. Cx43 in adult mouse hearts was coimmunoprecipitated using a TCTP-specific antibody. Additionally, co-localization of TCTP and Cx43 was demonstrated using a proximity ligation assay in iPS cell-derived human cardiomyocytes. TCTP silencing reduced the formation of Cx43 gap junction channels at the intercellular contacts between cardiomyocytes.Moreover, TCTP silencing significantly attenuated GJIC among cardiomyocytes. Interestingly, the development of ventricular arrhythmia was attenuated in cardiomyocyte-specific TCTPoverexpressing mice. Conclusions: These findings indicate that TCTP regulates GJIC. Thus, TCTP may be a therapeutic target for preventing Cx43-related pathogenesis.