Abstract
ABSTRACTGDE2 (also known as GDPD5) is a multispanning membrane phosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby promotes neuronal differentiation both in vitro and in vivo. GDE2 is a prognostic marker in neuroblastoma, while loss of GDE2 leads to progressive neurodegeneration in mice; however, its regulation remains unclear. Here, we report that, in immature neuronal cells, GDE2 undergoes constitutive endocytosis and travels back along both fast and slow recycling routes. GDE2 trafficking is directed by C-terminal tail sequences that determine the ability of GDE2 to cleave GPI-anchored glypican-6 (GPC6) and induce a neuronal differentiation program. Specifically, we define a GDE2 truncation mutant that shows aberrant recycling and is dysfunctional, whereas a consecutive deletion results in cell-surface retention and gain of GDE2 function, thus uncovering distinctive regulatory sequences. Moreover, we identify a C-terminal leucine residue in a unique motif that is essential for GDE2 internalization. These findings establish a mechanistic link between GDE2 neuronal function and sequence-dependent trafficking, a crucial process gone awry in neurodegenerative diseases.This article has an associated First Person interview with the first author of the paper.
Highlights
Glycosylphosphatidylinositol (GPI)-anchored proteins at the plasma membrane are involved in the regulation of many vital biological functions, including signal transduction, cell adhesion, intercellular communication and differentiation
GDE2 trafficking – constitutive endocytosis and recycling Initial pilot studies showed that in undifferentiated neuronal cells, GDE2 is enriched in recycling endosomes, strongly suggesting regulation by membrane trafficking (Matas-Rico et al, 2016)
We confirmed that GDE2 colocalized with the endogenous transferrin receptor (TfR), a prototypic cargo of the clathrin-dependent endocytosis route (Fig. S1C)
Summary
Glycosylphosphatidylinositol (GPI)-anchored proteins at the plasma membrane are involved in the regulation of many vital biological functions, including signal transduction, cell adhesion, intercellular communication and differentiation. F.S.-P., 0000-0001-8362-5281; M.v.V., 0000-0001-7545-198X; B.v.d.B., 00000003-1037-907X; A.P., 0000-0002-1151-6227; W.H.M., 0000-0001-7545-198X; E.M.-R., 0000-0003-0640-5511 Received 4 June 2019; Accepted 19 December 2019 leaflet of the plasma membrane, at lipid raft nanodomains (Ferguson et al, 2015; Fujita and Kinoshita, 2010; Paulick and Bertozzi, 2008). Since they lack a transmembrane domain, GPIanchored proteins cannot transmit signals by themselves but must interact with transmembrane effectors or cellular adhesion pathways to achieve signaling competence. Identification of the responsible phospholipase(s) and their biological function has long been elusive
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