Abstract
Alkenyl ether phospholipids are a major sub-class of ethanolamine- and choline-phospholipids in which a long chain fatty alcohol is attached at the sn-1 position through a vinyl ether bond. Biosynthesis of ethanolamine-containing alkenyl ether phospholipids, plasmalogens, is regulated by modulating the stability of fatty acyl-CoA reductase 1 (Far1) in a manner dependent on the level of cellular plasmalogens. However, precise molecular mechanisms underlying the regulation of plasmalogen synthesis remain poorly understood. Here we show that degradation of Far1 is accelerated by inhibiting dynamin-, Src kinase-, or flotillin-1-mediated endocytosis without increasing the cellular level of plasmalogens. By contrast, Far1 is stabilized by sequestering cholesterol with nystatin. Moreover, abrogation of the asymmetric distribution of plasmalogens in the plasma membrane by reducing the expression of CDC50A encoding a β-subunit of flippase elevates the expression level of Far1 and plasmalogen synthesis without reducing the total cellular level of plasmalogens. Together, these results support a model that plasmalogens localised in the inner leaflet of the plasma membranes are sensed for plasmalogen homeostasis in cells, thereby suggesting that plasmalogen synthesis is spatiotemporally regulated by monitoring cellular level of plasmalogens.
Highlights
That plasmalogens localised in the inner leaflet of the plasma membrane are sensed, of which signal is transferred to peroxisomes to modulate the stability of Far[1]
Dynamin-mediated endocytosis is involved in the regulation of plasmalogen synthesis
We suspected that plasmalogens in either ER or the post-Golgi compartments including plasma membrane are sensed for the regulation of plasmalogen synthesis
Summary
That plasmalogens localised in the inner leaflet of the plasma membrane are sensed, of which signal is transferred to peroxisomes to modulate the stability of Far[1]. Expression of Far[1] was lowered in ZPEG251 cells upon culturing with purified plasmalogens as compared to that in untreated ZPEG251, which was further reduced in the presence of Dynasore (Fig. 4A, lanes 1–3), confirming that inhibition of dynamin-mediated endocytosis induces degradation of Far[1] (Fig. 3A, lanes 2 and 3).
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