MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII

Konstantinidis, Klitos; Bezzerides, Vassilios J.; Lai, Lo; Isbell, Holly M.; Wei, An-Chi; Wu, Yuejin; Viswanathan, Meera; Blum, Ian D.; Granger, Jonathan M.; Heims-Waldron, Danielle A; Zhang, Donghui; Luczak, Elizabeth D.; Murphy, Kevin R.; Lu, Fujian; Gratz, Daniel; Manta, Bruno; Wang, Qiang; Wang, Qinchuan; Kolodkin, Alex L.; Gladyshev, Vadim N.; Hund, Thomas J.; Pu, William T.; Wu, Mark N.; Cammarato, Anthony; Bianchet, M.A.; Shea, Madeline A.; Levine, Rodney L.; Anderson, Mark E.

doi:10.1172/jci133181

Cited by 26 publications

(24 citation statements)

References 58 publications

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“…In addition to evidence from modeling suggesting that MM-fly CaMKII is a hyperactive enzyme in the presence of ROS, we recently reported a different line of flies harboring a hypomorphic CaMKII mutation 62 . Flies with the hypomorphic CaMKII show reduced activity and exhibit a striking reduction in heart tube contractility 62 , the opposite of the phenotype we observed in MM flies without NAC treatment. Taken together, these findings provide strong support that the MM module augments CaMKII activity in the presence of ROS.…”

Section: Methodsmentioning

confidence: 88%

CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution

et al. 2021

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Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca2+ and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates.

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Section: Methodsmentioning

confidence: 88%

CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution

et al. 2021

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“…Thus, investigations from a number of laboratories support the notion that reversible protein methionine sulfoxidation can act as an antioxidant buffer system [115][116][117][118]. In addition, methionine oxidation activates transcription factors in response to stimuli [119,120], regulates the cytoskeleton dynamics [121][122][123], and the activity of key signaling protein kinases [124,125], just to mention a few examples. The interconversion of Met and MetO also influences protein stability and protein-protein interactions (PPI) [76,126].…”

Section: Role Of Methionine Residues In Modulating Llpsmentioning

confidence: 97%

“…Finally, the sulfur atom of methionine can be readily oxidized to form methionine sulfoxide (MetO). This oxidation reaction can be catalyzed by enzymes [122,123,125,138]. However, the number of proteins proved to be oxidized in an enzyme-catalyzed reaction is very small.…”

Section: Short Overview On Methionine Properties Relevant For Llpsmentioning

confidence: 99%

“…However, the number of proteins proved to be oxidized in an enzyme-catalyzed reaction is very small. Although we can anticipate that this list will be extended in the future, only three proteins are included in it, namely calmodulin [138,139], F-actin [122,123], and Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) [125]. Nevertheless, hundreds of proteins are known to be sulfoxidized within living cells in response to oxidative stimuli [140].…”

Section: Short Overview On Methionine Properties Relevant For Llpsmentioning

confidence: 99%

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The Role of Methionine Residues in the Regulation of Liquid-Liquid Phase Separation

Aledo

2021

Biomolecules

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Membraneless organelles are non-stoichiometric supramolecular structures in the micron scale. These structures can be quickly assembled/disassembled in a regulated fashion in response to specific stimuli. Membraneless organelles contribute to the spatiotemporal compartmentalization of the cell, and they are involved in diverse cellular processes often, but not exclusively, related to RNA metabolism. Liquid-liquid phase separation, a reversible event involving demixing into two distinct liquid phases, provides a physical framework to gain insights concerning the molecular forces underlying the process and how they can be tuned according to the cellular needs. Proteins able to undergo phase separation usually present a modular architecture, which favors a multivalency-driven demixing. We discuss the role of low complexity regions in establishing networks of intra- and intermolecular interactions that collectively control the phase regime. Post-translational modifications of the residues present in these domains provide a convenient strategy to reshape the residue–residue interaction networks that determine the dynamics of phase separation. Focus will be placed on those proteins with low complexity domains exhibiting a biased composition towards the amino acid methionine and the prominent role that reversible methionine sulfoxidation plays in the assembly/disassembly of biomolecular condensates.

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“…However, posttranslational modifications can result in the prevention of reassociation between the regulatory and catalytic domains, thereby converting the enzyme to a persistently active state. These posttranslational modifications include autophosphorylation at Thr-287 ( Lai et al, 1987 ) and Thr-306/307 ( Patton et al, 1990 ; Lu et al, 2003 ), oxidation at Met-281/282 ( Erickson et al, 2008 ), and Met-308 ( Konstantinidis et al, 2020 ), O-GlcNAc modification at Ser-280 ( Erickson et al, 2013 ), and nitrosylation at Cys-290 ( Erickson et al, 2015 ; Figure 1 ). While posttranslational modifications in between the catalytic domain and the CaM binding site lead to autonomous activity, modifications within the CaM binding site, in contrast, appear to have an inhibitory effect.…”

Section: Ca 2+ /Calmodulin Dependent Protein Kinasmentioning

confidence: 99%

CaMKIIδ Splice Variants in the Healthy and Diseased Heart

Durán

Nickel

Estrada

et al. 2021

Front. Cell Dev. Biol.

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RNA splicing has been recognized in recent years as a pivotal player in heart development and disease. The Ca2+/calmodulin dependent protein kinase II delta (CaMKIIδ) is a multifunctional Ser/Thr kinase family and generates at least 11 different splice variants through alternative splicing. This enzyme, which belongs to the CaMKII family, is the predominant family member in the heart and functions as a messenger toward adaptive or detrimental signaling in cardiomyocytes. Classically, the nuclear CaMKIIδB and cytoplasmic CaMKIIδC splice variants are described as mediators of arrhythmias, contractile function, Ca2+ handling, and gene transcription. Recent findings also put CaMKIIδA and CaMKIIδ9 as cardinal players in the global CaMKII response in the heart. In this review, we discuss and summarize the new insights into CaMKIIδ splice variants and their (proposed) functions, as well as CaMKII-engineered mouse phenotypes and cardiac dysfunction related to CaMKIIδ missplicing. We also discuss RNA splicing factors affecting CaMKII splicing. Finally, we discuss the translational perspective derived from these insights and future directions on CaMKIIδ splicing research in the healthy and diseased heart.

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MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII

Abstract: Conflict of interest:MEA is a named inventor on patents claiming to treat heart disease by CaMKII inhibition. No income derives from these activities.

Cited by 26 publications

References 58 publications

CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution

CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution

The Role of Methionine Residues in the Regulation of Liquid-Liquid Phase Separation

CaMKIIδ Splice Variants in the Healthy and Diseased Heart

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