Myosin Vb mediates Cu+ export in polarized hepatocytes

Area of Science:

• Hepatology
• Cell Biology
• Molecular Medicine

Background:

• The mechanism for transporting the Wilson disease protein ATP7B to the hepatocyte apical domain, stimulated by copper (Cu+), is not well understood.
• ATP7B plays a critical role in cellular copper excretion.

Purpose of the Study:

• To investigate the role of myosin Vb in the Cu(+)-stimulated delivery of ATP7B to the apical domain of polarized hepatic cells.
• To determine the impact of disrupting the ATP7B-myosin Vb interaction on cellular copper export.

Main Methods:

• Utilized overexpression of the myosin Vb tail to disrupt cargo binding to myosin Vb.
• Analyzed the effect of myosin Vb tail expression on ATP7B surface expression and cellular Cu(+) export.
• Investigated the localization of ATP7B and myosin Vb in relation to intracellular apical compartments.

Main Results:

• Myosin Vb was identified as a regulator of Cu(+)-stimulated ATP7B delivery to the apical domain of polarized hepatic cells.
• Disruption of the ATP7B-myosin Vb interaction reduced apical ATP7B surface expression and impaired cellular Cu(+) export.
• Overexpression of the myosin Vb tail led to ATP7B accumulation in intracellular apical compartments, suggesting these are precursors for cargo transfer.

Conclusions:

• Myosin Vb is essential for the proper targeting and surface expression of ATP7B in hepatocytes, facilitating copper excretion.
• Dysfunction of myosin Vb may contribute to reduced hepatic copper clearance in idiopathic non-Wilsonian diseases.