ER-PM contacts regulate apical domain formation in hepatocytes
Posted on: 4 June 2020
Preprint posted on 24 April 2020
Membrane contacts meet cell polarity: ER-PM contacts are asymmetrically distributed in epithelial cells and contribute to lipid organisation
Selected by Helen ZennerCategories: cell biology, developmental biology
Background
Cells polarise by segregating their plasma membrane and cortical components into distinct domains. Enrichment of phosphatidylinositol 4,5 phosphate (PI(4,5)P2) and phosphatidylserine (PS) occurs at the forming apical domain in epithelial cells, and then is maintained once the cell is polarised. Both PI(4,5)P2 and PS are involved in recruiting apical polarity factors, including Cdc42 and Par complex. Surprisingly, how these lipids first accumulate asymmetrically is unknown.
Recently, extensive efforts have been made to characterise the proteins involved in lipid transfer at membrane contact sites throughout the cell. One of the best studied contacts is that between the plasma membrane (PM) and endoplasmic reticulum (ER). Two proteins found at these contacts, extended synaptotagmim protein-1 (E-Syt1) and oxysterol-binding protein related protein 5 (ORP5) have been shown to regulate PI(4,5)P2 and PS levels, although data for this is mixed. In this preprint, Chung et al. hypothesise that lipid transfer proteins (LTPs) play a role in setting up the lipid asymmetry in epithelial cells. This, of course, would require types of ER-PM contacts, or densities of contacts to be also be asymmetrically distributed within polarised cells.
Main findings
Analysing beautiful electron microscopy (EM) serial sections from mouse hepatocytes, the authors find striking differences in the density of ER-PM between the different plasma membrane domains. The polarity of hepatocytes in a little more complicated than ‘textbook’ epithelial cells but can be divided into equivalent domains of apical (that forms bile canaliculi, BC), lateral (cell-cell junctional zone) and basal. Quantification of the EM images shows 20% of the lateral membrane is associated with ER contact sites, whilst the basal membrane has a mere 5.4%, and the apical membrane only 0.6%. Furthermore, the extent and morphology of each contact varies substantially, where the average contact length on the lateral surface is four times greater than that observed for the apical contacts. Even within the lateral membrane the localisation of the contacts is not uniform suggesting they are under precise regulation. Similar data was observed in mouse renal inner medullary collecting duct spheroids.
Using hepatoblastoma couplets (liver derived cells that form polarised pairs), the authors then checked for a functional role of the LTPs E-Syt1 and ORP5 in apical domain establishment. Upon overexpression of a mutant of E-Syt1 assumed to be defective in Ca2+ dependent membrane tethering, fewer developing and mature stage couplets were observed. Coincident with this, intracellular accumulations of PS-positive membrane compartments were observed suggesting that E-Syt1 may be involved in transfer of PS to the plasma membrane. Overexpression of wild type ORP5 also impaired apical (BC) development. This supports a model where E-Syt1 and ORP5 are involved in regulated lipid composition during apical initiation as it is known that overexpression of wild type ORP5 reduces of the presence PI(4,5)P2 and PI(4)P at the plasma membrane. of impaired apical (BC) development.
Overall this paper provides exciting data suggesting that control of ER-PM contacts may be an upstream component of both polarity initiation and establishment in epithelial cells.
Questions for the authors
- Does overexpression of E-Syt1 or Orp5 have any impact of spheroid establishment or maintenance?
- The lateral and basal membranes are described in the literature to have similar lipid composition, but from this work very different densities of contacts, why might this be?
- Is the size of the contacts constrained by the morphology of the plasma membrane rather than by the composition of contacts?
- Why is the density of ER-PM contacts lowest at the apical membrane, where lipid composition is changing most during polarisation?
doi: https://doi.org/10.1242/prelights.21722
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