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MAP4 Regulates Tubulin to Control Cardiac Disease

Introduction

Microtubules (MTs) are long, tube-like structures formed by uniformly assembled conserved α/β-tubulin subunits 1. They are one of the main components of the eukaryotic cytoskeleton1. MTs interact with MT-associated proteins (MAPs) and assemble into specialized structures to perform diverse cellular functions 2. Specifically, they are critical in the assembly of mitotic and meiotic spindles, neuronal development, and the formation of the ciliary axoneme 2. MAPs are diverse groups of effector proteins that bind to the MTs within the cell, promoting their polymerization, stability, structure and function 2. MAPs have unique structures that are critical for their function in various cellular processes such as cell division, cell motility, intracellular organization, and trafficking of organelles, among others 3.

MAPs can be categorized into two main types: structural MAPs and molecular motors 4,5. Structural MAPs are crucial in the organization and stability of MT cytoskeleton 4. On the other hand, molecular motors facilitate molecules' movement along the MTs 4.  Structural MAPs —MAP2, tau, and MAP4— are well characterized and perform various functions 6,7. MAP2 and tau are mainly expressed in neuronal cells. In contrast, MAP4 is a cytosolic MT binding protein ubiquitously expressed in many cells and tissues and is critical for regulating MT dynamics 8,9. MAPs regulate tubulin dynamics through post-translational modifications (PTMs) 3,10; thus, tight regulation of tubulin PTMs is critical for proper function. This newsletter will explore MAP4's intricate role in controlling cardiac disease pathways through its control of tubulin dynamics.

MAP4 Regulation Mediates MT Dynamics in Cardiomyocytes.

Cardiomyocytes are specialized muscle cells found in the heart and responsible for the contraction of heart muscles. They are crucial in maintaining normal cardiovascular function and overall cardiac health 6. MAP4 is the most predominant MAP in cardiomyocytes11 and contributes to the structural organization and stability of the cardiomyocyte MT network by binding to α- and β-tubulin 4,5. Several studies have shown that tubulin undergoes various PTMs such as detyrosination/tyrosination, phosphorylation, glutamylation, glycylation, acetylation/deacetylation, polyamination, and palmitoylation to regulate MT dynamics and functions in cardiomyocytes 10,12. Interestingly, MAP4 phosphorylation/dephosphorylation affects its regulation of MT dynamics in cardiomyocytes 10,13. For example, Webster and Bratcher showed that MAP4 protein expression in cardiomyocytes regulated MT dynamics during heart development, with multiple isoforms contributing distinctly to MT-binding and bundling affinities 14. The authors highlighted that the low phosphorylation of MAP4 observed was most likely due to a large stable subset of MTs found in neonatal cardiomyocytes 14.  Another study showed that phosphorylation of MAP4 triggered by Microtubule-Affinity Regulating Kinase 4 (MARK4) led to MT instability by reducing its affinity for tubulin and promoting its disassembly in cardiomyocytes 6,10. Conversely, overexpression of MAP4 in the same conditions promoted the polymerization of MTs, stabilizing the MT networks within the cardiomyocytes 11. Similarly, MARK4 regulates cardiomyocyte contractility by promoting the phosphorylation of MAP4, facilitating the detyrosination of α-tubulin through Vasohibin 2 (VASH2) — a tubulin carboxypeptidase that catalyzes the removal of the terminal tyrosine residue from α-tubulin 12.  Additionally, MAP4 phosphorylation is linked to MT disruption under hypoxic conditions, affecting cell viability 15.  Altogether, the dynamic changes in MT assembly and disassembly regulated by MAP4 are crucial for maintaining the contractility, structural integrity and function of the MT network, which in turn impacts various cellular processes, including cell division, intracellular transport and cell shape maintenance in cardiomyocytes; ultimately, impacting cardiac health and function 10,12,15.

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Figure 1: Schematic demonstrating the role of MAP4 in cardiovascular disease under stressed or pathological conditions. Adapted from Li et al. 2020 6.

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MAP4 regulated Tubulin dysfunction in the development of cardiac disease.

Cardiac disease is the leading cause of death globally 5. It consists of a vast array of pathologies such as cardiomyopathies, arrhythmias, hypoxia/ischemia metabolic disease, hypertension and myocardial infarction, among others 4–6,16. MAP4 dysregulation has been implicated in many pathophysiological processes of heart disease — hypertrophy, ischemic cardiomyopathy, myocardial infarction, and heart failure 4,5 6,9. Interestingly, detyrosinated MTs are a common feature in various cardiac diseases, which results from the interaction of MAP4 with MTs 4,17. Moreover, detyrosinated MTs are linked with increased mechanical resistance by crosslinking with desmin intermediate filaments promoting myocyte stiffness. This myocyte stiffness impairs cardiomyocyte contractions, leading to pathological conditions5,10.  Accumulated evidence has implicated MAP4-regulated tubulin dysfunction in developing cardiac diseases 4–6,16.

Cardiac hypertrophy is characterized by an increase in the size of the heart muscle cells, leading to thickening of the heart walls. In an earlier study, MAP4 was upregulated in hypertrophic cardiomyocytes, and its dephosphorylation promoted MT stability and the progression of the disease 18.  Takahashi and colleagues found that overexpression of MAP4 had dual effects: it increased tubulin expression and stability while altering MT network characteristics. These changes were crucial in influencing pressure overload-induced cardiac hypertrophy phenotype 11. Proteomic analysis of the left ventricle showed that MAP4 was highly conserved and upregulated in human failing hearts compared to normal control 19 20. Furthermore, MAP4 interacts with MTs to inhibit the trafficking of β-adrenergic receptors (β-AR) in adult cardiomyocytes suggesting its role in downregulation of β-AR in pressure-overload cardiac hypertrophy 21.

Myocardial infarction is a major cause of premature death in adults. It is typically caused by myocardial ischemia 12. Post-acute ischaemic injury, the reduced affinity of MAP4 to MT is associated with increased tyrosinated MTs 5. Mechanistically, MARK4-induced phosphorylation of MAP4 facilitates access to tubulin vasohibin 2 (VASH2), leading to MT detyrosination in myocardial infarction, impairing the overall function of the heart 20.

In hypoxemic patients with Tetralogy of Fallot (TOF), there was a noticeable rise in MAP4 phosphorylation and cardiac apoptosis within hypertrophic right ventricular tissues compared to normoxemia patients with P38/MAPK signaling pathway mediating the phosphorylation of MAP4 9. This observation implies that MAP4 phosphorylation may contribute to hypoxia-induced cardiomyocyte apoptosis in clinical cases of TOF 9. Increased phosphorylated MAP4 (p-MAP4) plays a crucial role in the pathophysiological process of cardiac mitochondrial dysfunction and apoptosis in ischemic conditions (Figure 1) of heart failure and myocardial infarction 22,23. Altogether, these findings underscore the role of MAP4-regulated tubulin dysfunction in developing cardiac diseases.

Summary and Future Prospect

MAP4 regulation of tubulin plays a role in the maintenance of MT dynamics and structure, which is integral to the normal functioning of the cardiomyocytes critical for cardiac health. MAP4 regulation of MTs are mediated by MAP4-related signaling pathways or P38/MAPK interactions that induce post-translational modifications important for MT stability and cellular function. These PTMs maintain the balance between tubulin dimer polymerization and its disassembly. Disruption in this balance can have severe consequences and is associated with various human diseases.

Moving forward, MAP4 has been demonstrated to be critical in the pathogenesis of many cardiac diseases — cardiac hypertrophy, hypoxic myocardial injury, and MI-induced heart failure 6 However, the specific pathways, kinases, and interactions between MAP4 and its regulation of MTs are not fully elucidated. Therefore, further research is warranted into MAP4's regulatory mechanisms and their specific roles in different cardiac diseases. Investigating the signaling pathways, kinases, and molecular interactions that modulate MAP4 tubulin regulations and activity could uncover novel therapeutic targets for treating cardiac diseases. Additionally, exploring the potential of MAP4 as a biomarker for cardiac disease progression and therapeutic response could enhance diagnostic and prognostic strategies in clinical settings.

 

References

  1. Goodson, H. V. & Jonasson, E. M. Microtubules and microtubule-associated proteins. Cold Spring Harb Perspect Biol 10, (2018).
  2. Bodakuntla, S., Jijumon, A. S., Villablanca, C., Gonzalez-Billault, C. & Janke, C. Microtubule-Associated Proteins: Structuring the Cytoskeleton. Trends in Cell Biology vol. 29 804–819 Preprint at https://doi.org/10.1016/j.tcb.2019.07.004 (2019).
  3. Uchida, K., Scarborough, E. A. & Prosser, B. L. Cardiomyocyte Microtubules: Control of Mechanics, Transport, and Remodeling. Annu Rev Physiol 84, 257–283 (2022).
  4. Caporizzo, M. A. & Prosser, B. L. The microtubule cytoskeleton in cardiac mechanics and heart failure. Nature Reviews Cardiology 2022 19:6 19, 364–378 (2022).
  5. Warner, E. F., Li, Y. & Li, X. Targeting Microtubules for the Treatment of Heart Disease. Circ Res 130, 1723–1741 (2022).
  6. Li, L., Zhang, Q., Lei, X., Huang, Y. & Hu, J. MAP4 as a New Candidate in Cardiovascular Disease. Front Physiol 11, 564476 (2020).
  7. Nishida, K. et al. Effects of three microtubule-associated proteins (MAP2, MAP4, and Tau) on microtubules’ physical properties and neurite morphology. Scientific Reports 2023 13:1 13, 1–12 (2023).
  8. Feng, Y. hai et al. Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis. Cell Death Discovery 2021 7:1 7, 1–12 (2021).
  9. Li, L. et al. Microtubule associated protein 4 phosphorylation leads to pathological cardiac remodeling in mice. EBioMedicine 37, 221–235 (2018).
  10. Sanyal, C. et al. The detyrosination/re-tyrosination cycle of tubulin and its role and dysfunction in neurons and cardiomyocytes. Semin Cell Dev Biol 137, 46–62 (2023).
  11. Takahashi, M. et al. Phenotypic consequences of β1-tubulin expression and MAP4 decoration of microtubules in adult cardiocytes. Am J Physiol Heart Circ Physiol 285, 2072–2083 (2003).
  12. Scholz, D. et al. Microtubule-associated protein-4 (MAP-4) inhibits microtubule-dependent distribution of mRNA in isolated neonatal cardiocytes. Cardiovasc Res 71, 506–516 (2006).
  13. Li, X. et al. BS31 MARK4 controls ischaemic heart failure through microtubule detyrosination. Heart 108, A164–A164 (2022).
  14. Webster, D. R. & Bratcher, J. M. Developmental regulation of cardiac MAP4 protein expression. Cell Motil Cytoskeleton 63, 512–522 (2006).
  15. Hu, J. Y. et al. The p38/MAPK pathway regulates microtubule polymerization through phosphorylation of MAP4 and Op18 in hypoxic cells. Cellular and Molecular Life Sciences 67, 321–333 (2010).
  16. Chen, Q., Zhang, J., Song, Z. & Huang, Y. The Roles of Microtubule-Associated Protein 4 in Wound Healing and Human Diseases. Frontiers in Bioscience - Landmark 28, 76 (2023).
  17. Margulies, K. B. & Prosser, B. L. Tubulin Detyrosination: An Emerging Therapeutic Target in Hypertrophic Cardiomyopathy. Circ Heart Fail 14, e008006 (2021).
  18. Chinnakkannu, P. et al. Site-specific microtubule-associated protein 4 dephosphorylation causes microtubule network densification in pressure overload cardiac hypertrophy. Journal of Biological Chemistry 285, 21837–21848 (2010).
  19. Chen, C. Y. et al. Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure. Nature Medicine 2018 24:8 24, 1225–1233 (2018).
  20. Yu, X. et al. MARK4 controls ischaemic heart failure through microtubule detyrosination. Nature 2021 594:7864 594, 560–565 (2021).
  21. Cheng, G., Qiao, F., Gallien, T. N., Kuppuswamy, D. & Cooper, G. Inhibition of β-adrenergic receptor trafficking in adult cardiocytes by MAP4 decoration of microtubules. American Journal of Physiology-Heart and Circulatory Physiology 288, (2004).
  22. Li, L., Zhang, J., Zhang, Q., Huang, Y. & Hu, J. Cardiac proteomics reveals the potential mechanism of microtubule associated protein 4 phosphorylation-induced mitochondrial dysfunction. Burns Trauma 7, (2019).
  23. Hu, J. et al. Phosphorylation-dependent mitochondrial translocation of MAP4 is an early step in hypoxia-induced apoptosis in cardiomyocytes. Cell Death & Disease 2014 5:9 5, e1424–e1424 (2014).