ADP Ribosylation Factor 6 (ARF6) Promotes Acrosomal Exocytosis by Modulating Lipid Turnover and Rab3A Activation

Pelletán, Leonardo Enuar; Suhaiman, Laila; Vaquer, Cintia Celina; Bustos, Matías A.; Blas, Gerardo A. De; Vitale, Nicolas; Mayorga, Luis S.; Belmonte, Silvina

doi:10.1074/jbc.m114.629006

Cited by 33 publications

(29 citation statements)

References 91 publications

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“…Within this cascade, ARF6 promotes PLD activity and thus PA accumulation in the plasma membrane. The presence of PA is predicted to enhance membrane curvature of the inner leaflet of the plasma membrane, while also promoting formation of PI(4,5)P2 for SNARE complex association (Fig. ).…”

Section: Pa and Regulated Exocytosismentioning

confidence: 99%

“…Acrosomal exocytosis has been intensively studied and thus the signalling pathway culminating in plasma membrane fusion has been relatively well defined. Specifically, upon sperm activation, there is an increase in cytoplasmic calcium, which in turn activates an ARF6 signalling cascade that culminates in the assembly of SNARE complexes and subsequent membrane fusion and acrosome release . Within this cascade, ARF6 promotes PLD activity and thus PA accumulation in the plasma membrane.…”

Section: Pa and Regulated Exocytosismentioning

confidence: 99%

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A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa

Bullen

Soldati‐Favre

2016

FEBS Letters

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Edited by Wilhelm JustLipids are commonly known for the structural roles they play, however, the specific contribution of different lipid classes to wide-ranging signalling pathways is progressively being unravelled. Signalling lipids and their associated effector proteins are emerging as significant contributors to a vast array of effector functions within cells, including essential processes such as membrane fusion and vesicle exocytosis. Many phospholipids have signalling capacity, however, this review will focus on phosphatidic acid (PA) and the enzymes implicated in its production from diacylglycerol (DAG) and phosphatidylcholine (PC): DGK and PLD respectively. PA is a negatively charged, coneshaped lipid identified as a key mediator in specific membrane fusion and vesicle exocytosis events in a variety of mammalian cells, and has recently been implicated in specialised secretory organelle exocytosis in apicomplexan parasites. This review summarises the recent work implicating a role for PA regulation in exocytosis in various cell types. We will discuss how these signalling events are linked to pathogenesis in the phylum Apicomplexa.

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Section: Pa and Regulated Exocytosismentioning

confidence: 99%

Section: Pa and Regulated Exocytosismentioning

confidence: 99%

A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa

Bullen

Soldati‐Favre

2016

FEBS Letters

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“…Different approaches show both positive and negative roles for various members of the Rab3 family. Sperm Rab3A is activated (exchanges GDP for GTP) in the acrosomal region of human sperm in response to exocytosis inducers (22)(23)(24)(25). Later on, Rab3 must be inactivated (hydrolyze GTP) to accomplish vesiculation of the acrosomal and plasma membranes (26).…”

mentioning

confidence: 99%

The Rab3A-22A Chimera Prevents Sperm Exocytosis by Stabilizing Open Fusion Pores

Quevedo¹,

Lucchesi²,

Bustos³

et al. 2016

Journal of Biological Chemistry

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At the final stage of exocytotis, a fusion pore opens between the plasma and a secretory vesicle membranes; typically, when the pore dilates the vesicle releases its cargo. Sperm contain a large dense-core secretory granule (the acrosome) whose contents are secreted by regulated exocytosis at fertilization. Minutes after the arrival of the triggering signal, the acrosomal and plasma membranes dock at multiple sites and fusion pores open at the contact points. It is believed that immediately afterward, fusion pores dilate spontaneously. Rab3A is an essential component of human sperm exocytotic machinery. Yet, recombinant, persistently active Rab3A halts calcium-triggered secretion when introduced after docking into streptolysin O-permeabilized cells; so does a Rab3A-22A chimera. Here, we applied functional assays, electron and confocal microscopy to show that the secretion blockage is due to the stabilization of open fusion pores. Other novel findings are that sperm SNAREs engage in ␣-SNAP/NSF-sensitive complexes at a post-fusion stage. Complexes are disentangled by these chaperons to achieve vesiculation and acrosomal contents release. Thus, post-fusion regulation of the pores determines their expansion and the success of the acrosome reaction.

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“…As some of us have recently reported, membrane-impermeable MT inhibits acrosomal exocytosis in permeabilized sperm and interacts specifically with GTP-bound ADP-ribosylation factor 6. 40 First, in order to assess whether the chimeric membranepermeable CPP-MT was functionally active on its own, we performed standard exocytic assays under physiological conditions. The protein was coincubated with the cells at different concentrations (0.5-2 µM) and its effects were monitored by following the calcium-ionophore-triggered (A23187) acrosomal exocytosis process.…”

Section: Cpp-mt-aunp Inhibits Acrosomal Exocytosis In Human Spermmentioning

confidence: 99%

A TEM-traceable physiologically functional gold nanoprobe that permeates non-endocytic cells

Berberián¹,

Pocognoni²,

Mayorga³

2018

IJN

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BackgroundNanoparticles’ intracellular fate requires proper internalization. Most cells make use of a battery of internalization pathways, but some are practically sealed, as they lack the biochemical machinery for cellular intake. Non-endocytic cells, such as mammals’ spermatozoa, challenge standard drug-delivery strategies.PurposeIn this article, we present a gold nanoprobe that permeates the external and internal membranes of human sperm.MethodsOur design makes use of a gold nanoparticle functionalized with a membrane-permeable cysteine-rich recombinant protein. The chimeric protein contains two units of physiologically active metallothioneins (MT) that also provide binding motifs to gold and a cell-penetrating-peptide sequence (CPP) that confers cell permeability to the nanoparticle.ResultsTransmission electron microscopy, indirect immunofluorescence, and functional assays show that the nanoprobe is readily internalized in sperm, without compromising cell integrity, while preserving MT’s physiological activity. Our findings highlight the potential of CPP-functionalized nanogold for investigating the physiology of otherwise impermeable non-endocytic cells.

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ADP Ribosylation Factor 6 (ARF6) Promotes Acrosomal Exocytosis by Modulating Lipid Turnover and Rab3A Activation

Cited by 33 publications

References 91 publications

A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa

A central role for phosphatidic acid as a lipid mediator of regulated exocytosis in apicomplexa

The Rab3A-22A Chimera Prevents Sperm Exocytosis by Stabilizing Open Fusion Pores

A TEM-traceable physiologically functional gold nanoprobe that permeates non-endocytic cells

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