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Spectrin and Maladaptive Remodeling? STAT3: a link between CaMKII–βIV-spectrin and maladaptive remodeling? Mohit Hulsurkar, … , Ann P. Quick, Xander H.T. Wehrens J Clin Invest. 2018;128(12):5219-5221. https://doi.org/10.1172/JCI124778. Commentary 2+ βIV-Spectrin, along with ankyrin and Ca /calmodulin-dependent kinase II (CaMKII), has been shown to form local signaling domains at the intercalated disc, while playing a key role in the regulation of Na+ and K+ channels in cardiomyocytes. In this issue of the JCI, Unudurthi et al. show that under chronic pressure overload conditions, CaMKII activation leads to βIV-spectrin degradation, resulting in the release of sequestered STAT3 from the intercalated discs. This in turn leads to dysregulation of STAT3-mediated gene transcription, maladaptive remodeling, fibrosis, and decreased cardiac function. Overall, this study presents interesting findings regarding the role of CaMKII and βIV-spectrin under physiological as well as pathological conditions. Find the latest version: https://jci.me/124778/pdf The Journal of Clinical Investigation COMMENTARY STAT3: a link between CaMKII–βIV-spectrin and maladaptive remodeling? Mohit Hulsurkar,1,2 Ann P. Quick,1,2 and Xander H.T. Wehrens1,2,3,4,5,6 1Cardiovascular Research Institute, 2Department of Molecular Physiology and Biophysics, 3Department of Medicine, 4Department of Pediatrics, 5Department of Neuroscience, and 6Center for Space Medicine, Baylor College of Medicine, Houston, Texas, USA. In addition to their physiological roles, β-spectrins may also contribute to patho- β -Spectrin, along with ankyrin and Ca2+/calmodulin-dependent kinase IV logical changes during pressure over- II (CaMKII), has been shown to form local signaling domains at the load that precipitate detrimental cardiac intercalated disc, while playing a key role in the regulation of Na+ and remodeling. For instance, β -spectrin is + II K channels in cardiomyocytes. In this issue of the JCI, Unudurthi et al. cleaved by calpain-II during heart failure show that under chronic pressure overload conditions, CaMKII activation (5). However, it remains uncertain wheth- leads to βIV-spectrin degradation, resulting in the release of sequestered er the cleavage products further contrib- STAT3 from the intercalated discs. This in turn leads to dysregulation of ute to maladaptive cardiac remodeling in STAT3-mediated gene transcription, maladaptive remodeling, fibrosis, and addition to the degradation of βII-spectrin. decreased cardiac function. Overall, this study presents interesting findings Previous studies revealed that βIV-spectrin regarding the role of CaMKII and βIV-spectrin under physiological as well as is also decreased in human heart failure (7); pathological conditions. however, the role of βIV-spectrin in heart failure is yet to be completely understood. Spectrins modulate signaling One of the major functions of spectrins Spectrins in the cardiomyocyte several key ion channels including NCX, is to act as a hub for signaling molecules. cytoskeleton Na/K ATP-ase, Cav1.3 to T-tubules, IP3R Kinases, phosphatases, transcription fac- Cardiac function requires tightly reg- and RyR2 to the sarcoplasmic reticulum, tors, and other signaling molecules local- ulated signaling from the extracellular and Nav1.5 to intercalated discs (4). ize to subcellular domains containing spec- space to the cytoplasm across the plasma In their physiological role, spectrins trins (3). Previous studies have shown that membrane and from cell to cell across are required for maintenance of the car- an imbalance in kinase and phosphatase the intercalated disc. Efficient communi- diomyocyte ultrastructure and contractile activity can modulate ion channel activ- cation is achieved through organized ion function. βII-Spectrin conditional KO mice ity and promote arrhythmias and heart channel hubs known as microdomains develop cardiac dysfunction (5). Addi- failure (9). In addition to modulating ion that facilitate spatially and temporally tionally, spontaneous murine mutations channels, kinases and phosphatases that accurate signaling. These microdomains arising in βIV-spectrin known as quiver- localize to the spectrin scaffold can mod- are largely maintained by the cardiomyo- ing (qv) mice have revealed a critical role ulate β-spectrins themselves. Changes in 4J cyte cytoskeleton, which not only bolsters of βIV-spectrins (6). For instance, the qv the phosphorylation state of β-spectrins cardiomyocyte structure but also acts as mutation disrupts the interaction between can modulate membrane stability. For a scaffold for ion channels and signaling βIV-spectrin and ankyrin-G, thereby mislo- instance, enhanced β-spectrin phosphory- molecules. Spectrins are cytoskeletal pro- calizing the two-pore potassium channel lation disrupts membrane stability during teins with α and β isoforms that heterod- TREK1, which causes cardiac arrhythmias cellular remodeling events such as mitosis imerize and bind the actin cytoskeleton in mice (7). Likewise, qv3J mice lacking the (10). The consequences and downstream to a variety of membrane proteins (1). C-terminal CaMKII–βIV-spectrin interac- mechanisms of β-spectrin phosphorylation In cardiomyocytes, αII-spectrin dimeriz- tion develop disorganized and dysfunc- need further exploration in the context of es with βII-spectrin at the plasma mem- tional membranes in neuronal, pancreatic cardiomyocyte membrane stability and brane and sarcoplasmic reticulum (2) and (8), and cardiac muscle cells (3). These heart failure progression. with βIV-spectrin at the intercalated discs findings demonstrate the important phys- β-Spectrins also sequester other signal- (3). Through binding to adapter proteins iological role of cardiomyocyte ultrastruc- ing molecules including transcription fac- known as ankyrins, spectrins organize ture maintenance by β-spectrins. tors, such as SMAD3 (11) and YAP (12), and prevent their nuclear localization. In addi- tion to physical sequestration, transcription Related Article: p. 5561 factors are regulated by phosphorylation status. The JAK/STAT pathway is thought Conflict of interest: XHTW is a founding partner of Elex Biotech, a start-up company that develops drug molecules targeting ryanodine receptors for the treatment of cardiac arrhythmia disorders. to contribute to increased inflammation Reference information: J Clin Invest. 2018;128(12):5219–5221. https://doi.org/10.1172/JCI124778. in addition to cardiomyocyte hypertrophy. jci.org Volume 128 Number 12 December 2018 5219 COMMENTARY The Journal of Clinical Investigation pressure overload–induced remodeling and heart failure. However, the abolished CaMKII–βIV-spectrin interaction limits the localization of CaMKII to the membrane and inhibits its ability to phosphorylate other target proteins such as Kir6.2 (8) and Nav1.5 (3). Moreover, the protection afford- ed by the qv3J mutation is similar to that in total CaMKII–KO mice (18). Since CaMKII is known to be involved in multiple signal- ing pathways, a better understanding of the role of downstream proteins other than βIV-spectrin in CaMKII-mediated adverse remodeling is necessary. Future considerations Likewise, the specific molecular mecha- nisms of how CaMKII–βIV-spectrin result in an altered “statosome” and dysregula- tion of STAT3-mediated gene transcrip- tion are not known. Elaborate studies need to be planned to uncover the determinants of βIV-spectrin–STAT3 interaction and how STAT3 translocates into the nucleus upon β -spectrin degradation. In the canonical Figure 1. Schematic of the CaMKII/β -spectrin signaling axis at the cell membrane. CaMKII and IV IV pathway, STAT3 needs to be phosphory- βIV-spectrin bind to ankyrin-G (AnkG) and multiple ion channels such as Kir6.2 and Nav1.5 in the plasma membrane. In the present study, Unudurthi et al. show that, upon being phosphorylated by lated at Y705 and S727 to translocate into CaMKII, βIV-spectrin is degraded, which leads to STAT3 release and translocation into the nucleus, the nucleus (16). On the other hand, non- activating gene transcription in response to chronic stress. Some of the unanswered questions for canonical pathways are being identified, in future studies are highlighted in the black boxes in the figure. which STAT3 remains unphosphorylated (USTAT3) (16). This study did not con- sider the STAT3 phosphorylation status, Canonically, STAT3 is activated by JAK a novel CaMKII/βIV-spectrin/STAT3 path- but in the future it will be important to phosphorylation upon cytokine or angio- way that is activated in response to chronic distinguish whether STAT3 is phosphory- tensin signaling at the plasma membrane stress (Figure 1). This study is based on a lated at Y705 and/or S727 either directly and translocates to the nucleus, where it previous finding by the authors showing by CaMKII or indirectly through another acts as a transcription factor and cofactor that CaMKII and βIV-spectrin interact with kinase. An in-depth understanding of the (13). Although STAT3 nuclear translocation each other at the intercalated discs (3). In molecular mechanisms of STAT3 translo- has been shown to promote maladaptive this study, the authors show that βIV-spec- cation will be a critical stepping stone to remodeling including hypertrophy (13) trin binds to STAT3 under basal conditions developing βIV-spectrin and STAT3 as ther- and fibrosis, complete STAT3 KO in car- and sequesters it, forming a “statosome” at apeutic targets (Figure 1). Moreover, con- diomyocytes actually increases inflamma- the intercalated discs. Under chronic pres- tradictory data
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