Acylation – A New Means to Control Traffic Through the Golgi

Ernst, Andreas; Toomre, Derek; Bogan, Jonathan

doi:10.3389/fcell.2019.00109

Cited by 23 publications

(22 citation statements)

References 112 publications

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“…A recent review by Ernst et al (2019) demonstrated the importance of accounting for the spatial context of PATs, specifically PAT localization within distinct Golgi domains, to better understand anterograde sorting of specific substrates en route to the cell surface. With this in mind, we investigate in this review the possibility that PAT spatial context, or PAT subcellular localization, governs substrate targeting following substrate palmitoylation (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Spatial organization of palmitoyl acyl transferases governs substrate localization and function

Philippe

Jenkins

2019

Molecular Membrane Biology

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Protein palmitoylation is a critical posttranslational modification that regulates protein trafficking, localization, stability, sorting and function. In mammals, addition of this lipid modification onto proteins is mediated by a family of 23 palmitoyl acyl transferases (PATs). PATs often palmitoylate substrates in a promiscuous manner, precluding our understanding of how these enzymes achieve specificity for their substrates. Despite generous efforts to identify consensus motifs defining PAT-substrate specificity, it remains to be determined whether additional factors beyond interaction motifs, such as local palmitoylation, participate in PAT-substrate selection. In this review, we emphasize the role of local palmitoylation, in which substrates are palmitoylated and trapped in the same subcellular compartments as their PATs, as a mechanism of enzymesubstrate specificity. We focus here on non-Golgi-localized PATs, as physical proximity to their substrates enables them to engage in local palmitoylation, compared to Golgi PATs, which often direct trafficking of their substrates elsewhere. PAT subcellular localization may be an under-recognized, yet important determinant of PAT-substrate specificity that may work in conjunction or completely independently of interaction motifs. We also discuss some current hypotheses about protein motifs that contribute to localization of non-Golgi-localized PATs, important for the downstream targeting of their substrates.

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Section: Introductionmentioning

confidence: 99%

Spatial organization of palmitoyl acyl transferases governs substrate localization and function

Philippe

Jenkins

2019

Molecular Membrane Biology

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“…Our model is in agreement with the local S-palmitoylation described for substrates such as PSD95 at dendritic spines 38 and calnexin at the ER 47 , but adds the Golgi as a compartment in which PMPs can be locally modified and retained. To our knowledge, S-palmitoylation via the large number of Golgi-localized zDHHCs has been exclusively discussed in the context of Golgi-to-PM transport of integral 48 and PMPs 13 . We hereby challenge the current model and show instead that PMP localization to one compartment or another (including Golgi and PM) is not a consequence of sequential trafficking of the PMPs but rather a direct localization driven by the substrate-specific PAT activities at different compartments.…”

Section: Discussionmentioning

confidence: 99%

Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo

Solis

Valnohová

Álvarez

et al. 2020

Preprint

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Peripheral membrane proteins (PMPs) associate with cellular membranes through post-translational modifications like S-palmitoylation. The Golgi apparatus is generally viewed as the transitory station where palmitoyl acyltransferases (PATs) modify PMPs, which are then transported to their ultimate destinations such as plasma membrane (PM); little substrate specificity among the many PATs has been determined. Here we describe inherent partitioning of Gαo – α-subunit of heterotrimeric Go-proteins – to PM and Golgi, independent from Golgi-to-PM transport. A minimal code within the Gαo N-terminus governs the compartmentalization and re-coding produces G-protein versions with shifted localization. We established the SpONM (S-palmitoylation at the outer nuclear membrane) assay to probe substrate specificity of PATs in intact cells. With this assay, we showed that PATs localizing to different membrane compartments display remarkable substrate selectivity, which is the basis for specific PMP compartmentalization. Our findings uncover the fundamental mechanism governing protein localization and establish the basis for innovative drug discovery.

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“…First, palmitoylated C186 decreases the interaction with GDI1, hence impairs extraction of the mutant from the membrane resulting in a more stable interaction with membranes. Second, replacement of R186 by palmitoylated C186 should affect the membrane preference of Cdc42, both by removing a positively charged residue that favors the recognition of negatively charged phosphatidylinositides that are enriched at the plasma membrane 23 and by adding a lipid known to support trafficking through the Golgi (for example: reviewed in 28 ). Thus, both contributions are likely to determine why the Cdc42 mutant appears mostly trapped at the Golgi.…”

Section: Discussionmentioning

confidence: 99%

A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome

Bekhouche

Tourville

Ravichandran

et al. 2019

Preprint

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BackgroundAutoinflammatory diseases (AID) result from dysregulation of the first lines of innate immune responses. Recently, development of high throughput genome sequencing technology led to the rapid emergence of important knowledge in the genetic field. About 20 genes have been identified so far in monogenic forms of distinct AID. However, 70-90 % of patients with AID remain without genetic diagnosis. ObjectiveWe report the identification and characterization of a mutation in the C-terminal region of the Rho GTPase Cdc42 in a patient presenting a severe autoinflammatory phenotype. MethodsWe have analyzed the consequences of the mutation on the subcellular localization of the Cdc42 protein using imaging techniques. Molecular studies were performed using proteomic and biochemical experiments to provide mechanistic bases of the observed defects. Functional assays were also conducted using flow cytometry and cytokine production measurements. ResultsWe show that mutant Cdc42 is trapped in the Golgi apparatus due to the aberrant addition of a palmitate that both enhances the interaction of mutant Cdc42 with Golgi membranes and inhibit its extraction by GDP dissociation inhibitor (GDI), thus impairing its cytosol/membrane shuttling. At the functional level, mutant Cdc42 fails to sustain actin filaments polymerization and induces an exacerbated profile of pro-inflammatory cytokine production due to increased NF-B activation. ConclusionsOur study now provides a molecular explanation for mutations that have been identified recently in our AID patient and others in the C-terminal part of Cdc42. Mutations located in this region of Cdc42 impair the intracellular localization of Cdc42, preventing its interaction with the plasma membrane. Thus, our results definitively link mutations in the CDC42 gene to a complex immune-hemato-autoinflammatory phenotype in humans.

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Acylation – A New Means to Control Traffic Through the Golgi

Cited by 23 publications

References 112 publications

Spatial organization of palmitoyl acyl transferases governs substrate localization and function

Spatial organization of palmitoyl acyl transferases governs substrate localization and function

Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo

A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome

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