Abstract
Neuropathy target esterase (NTE) is an endoplasmic reticulum (ER)-localized phospholipase that deacylates phosphatidylcholine (PC) and lysophosphatidylcholine (LPC). Loss-of-function mutations in the human NTE gene have been associated with a spectrum of neurodegenerative disorders such as hereditary spastic paraplegia, ataxia and chorioretinal dystrophy. Despite this, little is known about structure–function relationships between NTE protein domains, enzymatic activity and the interaction with cellular organelles. In the current study we show that the C-terminal region of NTE forms a catalytically active domain that exhibits high affinity for lipid droplets (LDs), cellular storage organelles for triacylglycerol (TAG), which have been recently implicated in the progression of neurodegenerative diseases. Ectopic expression of the C domain in cultured cells decreases cellular PC, elevates TAG and induces LD clustering. LD interactions of NTE are inhibited by default by a non-enzymatic regulatory (R) region with three putative nucleotide monophosphate binding sites. Together with a N-terminal TMD the R region promotes proper distribution of the catalytic C-terminal region to the ER network. Taken together, our data indicate that NTE may exhibit dynamic interactions with the ER and LDs depending on the interplay of its functional regions. Mutations that disrupt this interplay may contribute to NTE-associated disorders by affecting NTE positioning.
Highlights
Neuropathy target esterase (NTE)— termed patatin-like phospholipase domain containing (PNPLA) 6—was identified as a principal target of organophosphates that cause a delayed neuropathy characterized by the degeneration of long axons and the paralysis of the lower limbs [1,2,3,4]
We first analyzed the subcellular distribution of full length NTE, the N-terminal transmembrane domain (TMD) and the R-region fused to GFP (NTE-GFP, NTETM-GFP and NTER-GFP, Figure 1A)
NTER-GFP exhibited a diffuse cytosolic distribution and did not coincide with the endoplasmic reticulum (ER). These results show that the N-terminal TMD but not the R-region is sufficient to target cytosolic
Summary
Neuropathy target esterase (NTE)— termed patatin-like phospholipase domain containing (PNPLA) 6—was identified as a principal target of organophosphates that cause a delayed neuropathy characterized by the degeneration of long axons and the paralysis of the lower limbs [1,2,3,4]. Lysophosphatidylcholine (LPC) and that organophosphate-induced neuropathy was most likely caused by the inhibition of NTE activity and a resultant disruption of membrane homeostasis [5,6,7,8,9]. Global disruption of the Nte/Pnpla gene in mice causes embryonic death due to placental failure and impaired vasculogenesis [11]. Apart from this, NTE is required for neuronal development, including adult axon maintenance and glial ensheathment of Remak fibers [12,13]
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