A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6

McGrath, Kaitlyn; Tonelli, Marco; Dergai, Mykola; Gaeta, Anthony L.; Shum, Andrew; Lacoste, Jessica; Zhang, Yongbo; Wen, Wenyu; Chung, Daayun; Wiersum, G.; Shevade, Aishwarya; Zaichick, Sofia; Rossum, Damian B. van; Shuvalova, L.; Savas, Jeffrey N.; Kuchin, Sergei; Taipale, Mikko; Caldwell, Kim A.; Fasshauer, Dirk; Caraveo, Gabriela

doi:10.1073/pnas.2016730118

Cited by 13 publications

(16 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The second study examines serine 174 of YKT6 (serine 176 in the yeast orthologue Ykt6). Specifically, the authors also demonstrate that this residue must be phosphorylated in order for YKT6 to switch from a closed, cytosolic form to an open, membrane-bound form (McGrath et al, 2021). They show that this phosphorylation occurs in response to Ca 2+ signalling and is required for the role of YKT6 in trafficking along the secretory pathway, from the ER and Golgi, in human cells.…”

Section: Snare Regulation Through Phosphorylationmentioning

confidence: 86%

See 1 more Smart Citation

Rerouting trafficking circuits through posttranslational SNARE modifications

Warner

Mahajan

Bogaart

2022

Journal of Cell Science

View full text Add to dashboard Cite

Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are membrane-associated trafficking proteins that confer identity to lipid membranes and facilitate membrane fusion. These functions are achieved through the complexing of Q-SNAREs with a specific cognate target R-SNARE, leading to the fusion of their associated membranes. These SNARE complexes then dissociate so that the Q-SNAREs and R-SNAREs can repeat this cycle. Whilst the basic function of SNAREs has been long appreciated, it is becoming increasingly clear that the cell can control the localisation and function of SNARE proteins through posttranslational modifications (PTMs), such as phosphorylation and ubiquitylation. Whilst numerous proteomic methods have shown that SNARE proteins are subject to these modifications, little is known about how these modifications regulate SNARE function. However, it is clear that these PTMs provide cells with an incredible functional plasticity; SNARE PTMs enable cells to respond to an ever-changing extracellular environment through the rerouting of membrane traffic. In this Review, we summarise key findings regarding SNARE regulation by PTMs and discuss how these modifications reprogramme membrane trafficking pathways.

show abstract

Section: Snare Regulation Through Phosphorylationmentioning

confidence: 86%

“…Two recent studies have identified conserved phosphorylation events on the R-SNARE YKT6 (Pradhipa Karuna et al, 2020;McGrath et al, 2021). YKT6 is an unusual SNARE, because it is extensively regulated through palmitoylation, geranylgeranylation and farnesylation.…”

Section: Snare Regulation Through Phosphorylationmentioning

confidence: 99%

Rerouting trafficking circuits through posttranslational SNARE modifications

Warner

Mahajan

Bogaart

2022

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…There may be regulation at the level of mediator release by the soluble NSF attachment protein family as different members have roles in packaging, intracellular trafficking, and extracellular secretion of cytokines and chemokines [ 40 ]. A precedent has been published showing calcineurin is crucial in exocytotic processes through interactions with soluble NSF attachment family members [ 41 , 42 ], with the latter implicated in release of mediators by activated MCs.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation

Leong¹,

Pang²,

Stadnyk³

et al. 2021

J Innate Immun

View full text Add to dashboard Cite

Mast cells (MCs) are key mediators of allergic inflammation through the activation of cross-linked immunoglobulin E (IgE) bound to the high-affinity IgE receptor (FcϵRI) on the cell surface, leading to the release of biologically potent mediators, either from preformed granules or newly synthesized. Pharmacological inhibitors have been developed to target a key signaling protein phosphatase in this pathway, calcineurin, yet there is a lack of genetic and definitive evidence for the various isoforms of calcineurin subunits in FcϵRI-mediated responses. In this study, we hypothesized that deficiency in the calcineurin Aα isoform will result in a decreased allergic immune response by the MCs. In a model of passive cutaneous anaphylaxis, there was a reduction in vascular permeability in MC-deficient mouse tissues reconstituted with calcineurin subunit A (CnAα) gene-knockout (CnAα−/−) MCs, and in vitro experiments identified a significant reduction in release of preformed mediators from granules. Furthermore, released levels of de novo synthesized cytokines were reduced upon FcϵRI activation of CnAα−/− MCs in vitro. Characterizing the mechanisms associated with this deficit response, we found a significant impairment of nuclear factor of kappa light polypeptide gene enhancer in B cell phosphorylation and impaired nuclear factor kappa-light-chain-enhancer of activated B-cell inhibitor alpha (NF-κB) activation. Thus, we concluded that CnAα contributes to the release of preformed mediators and newly synthesized mediators from FcϵRI-mediated activation of MCs, and this regulation includes NF-κB signaling.

show abstract

“…Phosphorylation of Ykt6 modulates its interactions in a Parkinson's disease model, suggesting a potential involvement of this longin also in PD [129]. Indeed, Parkinson's disease α-synuclein perturbs the physiological response to lysosomal stress by impeding Ykt6 [130].…”

Section: Snare and Tethering Factorsmentioning

confidence: 99%

Nuclear and Cytoplasmatic Players in Mitochondria-Related CNS Disorders: Chromatin Modifications and Subcellular Trafficking

et al. 2022

View full text Add to dashboard Cite

Aberrant mitochondrial phenotypes are common to many central nervous system (CNS) disorders, including neurodegenerative and neurodevelopmental diseases. Mitochondrial function and homeostasis depend on proper control of several biological processes such as chromatin remodeling and transcriptional control, post-transcriptional events, vesicle and organelle subcellular trafficking, fusion, and morphogenesis. Mutation or impaired regulation of major players that orchestrate such processes can disrupt cellular and mitochondrial dynamics, contributing to neurological disorders. The first part of this review provides an overview of a functional relationship between chromatin players and mitochondria. Specifically, we relied on specific monogenic CNS disorders which share features with mitochondrial diseases. On the other hand, subcellular trafficking is coordinated directly or indirectly through evolutionarily conserved domains and proteins that regulate the dynamics of membrane compartments and organelles, including mitochondria. Among these “building blocks”, longin domains and small GTPases are involved in autophagy and mitophagy, cell reshaping, and organelle fusion. Impairments in those processes significantly impact CNS as well and are discussed in the second part of the review. Hopefully, in filling the functional gap between the nucleus and cytoplasmic organelles new routes for therapy could be disclosed.

show abstract

A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6

Cited by 13 publications

References 50 publications

Rerouting trafficking circuits through posttranslational SNARE modifications

Rerouting trafficking circuits through posttranslational SNARE modifications

Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation

Nuclear and Cytoplasmatic Players in Mitochondria-Related CNS Disorders: Chromatin Modifications and Subcellular Trafficking

Contact Info

Product

Resources

About