Abstract:Highlights d NCX1 is dynamically palmitoylated at the cell surface by zDHHC5 and APT1 d Palmitoylation modifies the NCX1 dimer's structure and affinity for lipid rafts d We identify the binding site of the endogenous XIP domain in NCX1's regulatory loop d Palmitoylation modifies NCX1 XIP affinity and hence regulates intracellular Ca
“…G i α13 is obviously not the sole APT1 substrate. Since we began this project, several additional substrates have been reported: the microtubule-associated protein 6 MAP6 ( 45 ), the CD36 receptor ( 46 ), R-RAS ( 47 ), and the Na/Ca exchanger NCX1 ( 48 ). Last, an unbiased approach recently identified 382 potential APT1 substrates, although these have yet to be validated in vivo ( 49 ).…”
Huntington disease (HD) damages the corticostriatal circuitry in large part by impairing transport of brain-derived neurotrophic factor (BDNF). We hypothesized that improving vesicular transport of BDNF could slow or prevent disease progression. We therefore performed selective proteomic analysis of vesicles transported within corticostriatal projecting neurons followed by in silico screening and identified palmitoylation as a pathway that could restore defective huntingtin-dependent trafficking. Using a synchronized trafficking assay and an HD network-on-a-chip, we found that increasing brain palmitoylation via ML348, which inhibits the palmitate-removing enzyme acyl-protein thioesterase 1 (APT1), restores axonal transport, synapse homeostasis, and survival signaling to wild-type levels without toxicity. In human HD induced pluripotent stem cell–derived cortical neurons, ML348 increased BDNF trafficking. In HD knock-in mice, it efficiently crossed the blood-brain barrier to restore palmitoylation levels and reverse neuropathology, locomotor deficits, and anxio-depressive behaviors. APT1 and its inhibitor ML348 thus hold therapeutic interest for HD.
“…G i α13 is obviously not the sole APT1 substrate. Since we began this project, several additional substrates have been reported: the microtubule-associated protein 6 MAP6 ( 45 ), the CD36 receptor ( 46 ), R-RAS ( 47 ), and the Na/Ca exchanger NCX1 ( 48 ). Last, an unbiased approach recently identified 382 potential APT1 substrates, although these have yet to be validated in vivo ( 49 ).…”
Huntington disease (HD) damages the corticostriatal circuitry in large part by impairing transport of brain-derived neurotrophic factor (BDNF). We hypothesized that improving vesicular transport of BDNF could slow or prevent disease progression. We therefore performed selective proteomic analysis of vesicles transported within corticostriatal projecting neurons followed by in silico screening and identified palmitoylation as a pathway that could restore defective huntingtin-dependent trafficking. Using a synchronized trafficking assay and an HD network-on-a-chip, we found that increasing brain palmitoylation via ML348, which inhibits the palmitate-removing enzyme acyl-protein thioesterase 1 (APT1), restores axonal transport, synapse homeostasis, and survival signaling to wild-type levels without toxicity. In human HD induced pluripotent stem cell–derived cortical neurons, ML348 increased BDNF trafficking. In HD knock-in mice, it efficiently crossed the blood-brain barrier to restore palmitoylation levels and reverse neuropathology, locomotor deficits, and anxio-depressive behaviors. APT1 and its inhibitor ML348 thus hold therapeutic interest for HD.
“…It will be of particular interest to study the kinetics of S-acylation in relation to subsequent molecular and cellular events. For example, by using fluorescence resonance energy transfer (FRET) in live cells, it was recently found that the dynamic palmitoylation of sodium-calcium exchanger 1 (NCX1) leads to rearrangement of the f-loop region and regulate its dimerization ( Gök et al, 2020 ). These acylation-induced changes are key in recruiting the exchange inhibitory peptide and mediating Ca 2+ influx.…”
Section: Functional Outcomes Of S-acylationmentioning
Protein S-acylation is the reversible addition of fatty acids to the cysteine residues of target proteins. It regulates multiple aspects of protein function, including the localization to membranes, intracellular trafficking, protein interactions, protein stability, and protein conformation. This process is regulated by palmitoyl acyltransferases that have the conserved amino acid sequence DHHC at their active site. Although they have conserved catalytic cores, DHHC enzymes vary in their protein substrate selection, lipid substrate preference, and regulatory mechanisms. Alterations in DHHC enzyme function are associated with many human diseases, including cancers and neurological conditions. The removal of fatty acids from acylated cysteine residues is catalyzed by acyl protein thioesterases. Notably, S-acylation is now known to be a highly dynamic process, and plays crucial roles in signaling transduction in various cell types. In this review, we will explore the recent findings on protein S-acylation, the enzymatic regulation of this process, and discuss examples of dynamic S-acylation.
“…Similarly, the S-acyl chains (either at cysteine-166 or other sites in the channel) might also mediate specific interactions with membrane lipids, which could alter membrane micro-localization, and this will be interesting to explore in future work. Effects of S-acylation on protein interaction with cholesterol-rich lipid-ordered domains at the plasma membrane have been documented for a number of transmembrane proteins, including the sodium–calcium exchanger NCX1, which displays S-acylation-dependent accumulation in lipid-ordered domains that is linked to transporter function [ 32 ].…”
Section: Insulin Secretionmentioning
confidence: 99%
“…Thus, it will be interesting to examine if S-acylation increases the preference of the insulin receptor for a lipid-ordered membrane environment and if this contributes to caveolar association [ 90 ]. As a starting point, the relative association of wild-type and S-acylation-null receptor with ordered and disordered domains in giant plasma membrane vesicles could be assessed [ 32 ]. Figure 3 S-acylation of components of the insulin signalling and IRV exocytosis pathways.…”
Section: Insulin Signalling and Glut4 Vesicle Exocytosismentioning
Post-translational modifications (PTMs) such as phosphorylation and ubiquitination are well-studied events with a recognized importance in all aspects of cellular function. By contrast, protein S-acylation, although a widespread PTM with important functions in most physiological systems, has received far less attention. Perturbations in S-acylation are linked to various disorders, including intellectual disability, cancer and diabetes, suggesting that this less-studied modification is likely to be of considerable biological importance. As an exemplar, in this review, we focus on the newly emerging links between S-acylation and the hormone insulin. Specifically, we examine how S-acylation regulates key components of the insulin secretion and insulin response pathways. The proteins discussed highlight the diverse array of proteins that are modified by S-acylation, including channels, transporters, receptors and trafficking proteins and also illustrate the diverse effects that S-acylation has on these proteins, from membrane binding and micro-localization to regulation of protein sorting and protein interactions.
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