Rab11a and myosin Vb are required for bile canalicular formation in WIF-B9 cells.
Journal: 2005/December - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
Hepatocytes polarize by forming functionally distinct sinusoidal (basolateral) and canalicular (apical) plasma membrane domains. Two distinct routes are used for delivery of membrane proteins to the canaliculus. Proteins having glycosylphosphatidylinositol anchors or single transmembrane domains are targeted to the sinusoidal plasma membrane from where they transcytose to the canalicular domain. In contrast, apical ATP-binding-cassette (ABC) transporters, which are required for energy-dependent biliary secretion of bile acids (ABCB11), phospholipids (ABCB4), and nonbile acid organic anions (ABCC2), lack initial residence in the basolateral plasma membrane and traffic directly from Golgi membranes to the canalicular membrane. While investigating mechanisms of apical targeting in WIF-B9 cells, a polarized hepatic epithelial cell line, we observed that rab11a is required for canalicular formation. Knockdown of rab11a or overexpression of the rab11a-GDP locked form prevented canalicular formation as did overexpression of the myosin Vb motorless tail domain. In WIF-B9 cells, which lack bile canaliculi, apical ABC transporters colocalized with transcytotic membrane proteins in rab11a-containing endosomes and, unlike the transcytotic markers, did not distribute to the plasma membrane. We propose that polarization of hepatocytes (i.e., canalicular biogenesis) requires recruitment of rab11a and myosin Vb to intracellular membranes that contain apical ABC transporters and transcytotic markers, permitting their targeting to the plasma membrane. In this model, polarization is initiated upon delivery of rab11a-myosin Vb-containing membranes to the surface, which causes plasma membrane at the site of delivery to differentiate into apical domain (bile canaliculus).
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Proc Natl Acad Sci U S A 102(42): 15087-15092

Rab11a and myosin Vb are required for bile canalicular formation in WIF-B9 cells

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and Department of Physiology, Tufts University School of Medicine, Boston, MA 02111
To whom correspondence may be addressed. E-mail: vog.hin.liam@oyabakaw or vog.hin.liam@isaira.
Edited by David D. Sabatini, New York University School of Medicine, New York, NY, and approved September 8, 2005
Edited by David D. Sabatini, New York University School of Medicine, New York, NY, and approved September 8, 2005
Received 2005 May 4

Abstract

Hepatocytes polarize by forming functionally distinct sinusoidal (basolateral) and canalicular (apical) plasma membrane domains. Two distinct routes are used for delivery of membrane proteins to the canaliculus. Proteins having glycosylphosphatidylinositol anchors or single transmembrane domains are targeted to the sinusoidal plasma membrane from where they transcytose to the canalicular domain. In contrast, apical ATP-binding-cassette (ABC) transporters, which are required for energy-dependent biliary secretion of bile acids (ABCB11), phospholipids (ABCB4), and nonbile acid organic anions (ABCC2), lack initial residence in the basolateral plasma membrane and traffic directly from Golgi membranes to the canalicular membrane. While investigating mechanisms of apical targeting in WIF-B9 cells, a polarized hepatic epithelial cell line, we observed that rab11a is required for canalicular formation. Knockdown of rab11a or overexpression of the rab11a-GDP locked form prevented canalicular formation as did overexpression of the myosin Vb motorless tail domain. In WIF-B9 cells, which lack bile canaliculi, apical ABC transporters colocalized with transcytotic membrane proteins in rab11a-containing endosomes and, unlike the transcytotic markers, did not distribute to the plasma membrane. We propose that polarization of hepatocytes (i.e., canalicular biogenesis) requires recruitment of rab11a and myosin Vb to intracellular membranes that contain apical ABC transporters and transcytotic markers, permitting their targeting to the plasma membrane. In this model, polarization is initiated upon delivery of rab11a-myosin Vb-containing membranes to the surface, which causes plasma membrane at the site of delivery to differentiate into apical domain (bile canaliculus).

Keywords: hepatocyte polarization, plasma membrane segregation
Abstract

Polarization of hepatocytes involves formation of functionally distinct sinusoidal (basolateral) and canalicular (apical) plasma membrane domains that are separated by tight junctions. Bile is secreted across the canalicular membrane. Apical ATP binding cassette (ABC) transporters are required for energy-dependent biliary secretion of bile acids [bile salt export pump (BSEP) and ABCB11] (1), phospholipids (MDR3 and ABCB4) (2), sterols (ABCG5 and ABCG8) (3), and nonbile acid organic anions (MRP2 and ABCC2) (4, 5). Insufficient amounts of ABC transporters in the canalicular membrane impair biliary secretion, resulting in cholestasis (i.e., bile secretory failure) (6).

Canalicular membrane proteins use two distinct delivery routes from Golgi membranes. Proteins having glycosylphosphatidylinositol anchors or single transmembrane domains are targeted to the sinusoidal plasma membrane and subsequently undergo transcytosis to the canalicular domain (7, 8). In contrast, newly synthesized apical ABC transporter traffic from the Golgi membranes to the canalicular membrane without initial residence in the sinusoidal plasma membrane (911). Studies in WIF-B9 cells, a polarized hepatic epithelial cell line (12, 13), revealed that apical ABC transporters colocalize with rab11a and constitutively cycle between rab11a-positive endosomes and the canalicular membrane (14).

Because rab11a has been implicated in apical targeting in polarized epithelial cells (1517), we used WIF-B9 cells to determine its role in constitutive apical cycling and canalicular biogenesis.

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Acknowledgments

We thank Michael Veilleux for virus preparations and Janet Larkin for critical reading and suggestions. This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-54785 and DK-35652 (to I.M.A.).

Acknowledgments

Notes

Author contributions: Y.W., J.L.-S., and I.M.A. designed research; Y.W. and P.D. performed research; Y.W. analyzed data; and Y.W., J.L.-S., and I.M.A. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: ABC transporter, ATP binding cassette transporters; BSEP, bile salt export pump; cCAM105, cell adhesion molecule 105; CFP, cyan fluorescent protein; 5′NT, 5′nucleotidase; YFP, yellow fluorescent protein.

Notes
Author contributions: Y.W., J.L.-S., and I.M.A. designed research; Y.W. and P.D. performed research; Y.W. analyzed data; and Y.W., J.L.-S., and I.M.A. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ABC transporter, ATP binding cassette transporters; BSEP, bile salt export pump; cCAM105, cell adhesion molecule 105; CFP, cyan fluorescent protein; 5′NT, 5′nucleotidase; YFP, yellow fluorescent protein.

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