Myosin Vb mediates Cu+ export in polarized hepatocytes

Abstract

The cellular machinery responsible for Cu + -stimulated delivery of the Wilson-disease-associated protein ATP7B to the apical domain of hepatocytes is poorly understood. We demonstrate that myosin Vb regulates the Cu + -stimulated delivery of ATP7B to the apical domain of polarized hepatic cells, and that disruption of the ATP7B-myosin Vb interaction reduces the apical surface expression of ATP7B. Overexpression of the myosin Vb tail, which competes for binding of subapical cargos to myosin Vb bound to subapical actin, disrupted the surface expression of ATP7B, leading to reduced cellular Cu + export. The myosin-Vb-dependent targeting step occurred in parallel with hepatocyte-like polarity. If the myosin Vb tail was expressed acutely in cells just prior to the establishment of polarity, it appeared as part of an intracellular apical compartment, centered on γ-tubulin. ATP7B became selectively arrested in this compartment at high [Cu + ] in the presence of myosin Vb tail, suggesting that these compartments are precursors of donor-acceptor transfer stations for apically targeted cargos of myosin Vb. Our data suggest that reduced hepatic Cu + clearance in idiopathic non-Wilsonian types of disease might be associated with the loss of function of myosin Vb.

MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma

“…After 3 h, MAL2 surface labeling was lost with increased staining observed in the apical compartment, a structure that labels exclusively for apical membrane proteins in nonpolarized cells as we and other have previously extensively described ( Figure 5B(c)) [26]. After 4 h, labeling at the "apical compartment" and cell surface were observed consistent with the recycling reported for apical residents between these two compartments in nonpolarized cells also as we have previously described ( Figure 5B(d)) [26][27][28].…”

From and to the Golgi – defining the Wilson disease protein road map

“…Another molecular player has been recently reported to drive apical targeting of ATP7B. Myosin Vb has been demonstrated to participate in the delivery of ATP7B to the apical domain of polarized hepatic cells exposed to Cu, while disruption of the ATP7B/myosin Vb interaction significantly impaired apical expression of ATP7B . Thus, the apical delivery of ATP7B might be coordinated by p62/DNCT4 and myosin Vb motors by moving ATP7B‐containing organelles along microtubules and actin filaments, respectively .…”

The Relationship Between Actin Cytoskeleton and Membrane Transporters in Cisplatin Resistance of Cancer Cells

“…One of the answers is that F-actin regulates the expression and function of membrane transporters involved in cisplatin transport. The previous reports demonstrated that the rearrangement of F-actin increased the expression of cisplatin importer CTR1 (Abdellatef et al, 2015) and that the translocation of cisplatin exporters, ABC7A and ABC7B, from the trans-Golgi network to the plasma membrane is regulated by the formation of F-actin (Cobbold et al, 2002;Gupta et al, 2016). It is well known that the actin cytoskeleton regulates the VSOR anion channels, which contributes to cisplatin influx and sustained cell shrinkage during early apoptosis.…”