Here we show that deficiency of microtubule-affinity regulating kinase 4 (MARK4) substantially limits the reduction in the left ventricular ejection fraction after acute myocardial infarction in mice, without affecting infarct size or cardiac remodelling. Mechanistically, we provide evidence that MARK4 regulates cardiomyocyte contractility by promoting phosphorylation of microtubule-associated protein 4 (MAP4), which facilitates the access of vasohibin 2 (VASH2)-a tubulin carboxypeptidase-to microtubules for the detyrosination of α-tubulin. Our results show how the detyrosination of microtubules in cardiomyocytes is finely tuned by MARK4 to regulate cardiac inotropy, and identify MARK4 as a promising therapeutic target for improving cardiac function after myocardial infarction.
Myocardial infarction-the main cause of ischaemic heart disease and chronic heart failure-is a serious ischaemic syndrome in which the blood supply to the heart is blocked, thus causing substantial death of myocardial cells and loss of function in the remaining viable cells 6. Microtubule detyrosination, which is associated with desmin at force-generating sarcomeres 5, is upregulated in failing hearts of patients with ischaemic cardiomyopathy 5, 7 and hypertrophic cardiomyopathies 5, 7, 8, and suppression of microtubule detyrosination improves contractility in failing cardiomyocytes 7. VASH1 or VASH2, coupled to a small vasohibin-binding protein (SVBP), forms tubulin carboxypeptidases (TCPs) that are capable of tubulin detyrosination 9, 10. Depletion of VASH1 increases the speed of contraction and relaxation in failing human cardiomyocytes 11. Structural and biophysical studies have suggested that VASH interacts with the C-terminal tail of α-tubulin 12, 13, 14. However, the regulatory mechanisms of this system are still poorly understood. Microtubule stability is regulated by microtubule-associated proteins (MAPs), including classical MAPs such as MAP2, MAP4 and tau 15. MAP4 is expressed in cardiomyocytes and the level of MAP4 significantly increases in human hearts with cardiomyopathy 7. MAP4 dephosphorylation on the microtubule network has previously been described in a feline model of pressure-overload cardiac hypertrophy 16, but the relationship between MAP4 phosphorylation and microtubule detyrosination has not been examined. MARK4 is an evolutionarily conserved serine–threonine kinase 17, 18 that is known to phosphorylate MAPs including tau, MAP2 and MAP4, on KXGS motifs within their microtubule-binding repeats 19, 20, 21.
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