Plasma Membrane-associated Annexin A6 Reduces Ca2+ Entry by Stabilizing the Cortical Actin Cytoskeleton

Monastyrskaya, Katia; Babiychuk, Eduard B.; Hostettler, Andrea; Wood, Peta; Grewal, Thomas; Draeger, Annette

doi:10.1074/jbc.m109.004457

Cited by 65 publications

(74 citation statements)

References 57 publications

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“…Other studies (18) have shown that the inhibition of glucose transport and oxidation that cytochalasin B causes in rat islets occurs in non-␤-cells. We tentatively suggest that the longer fall in [Ca 2ϩ ] c , also observed with latrunculin B (not shown), could reflect an influence of actin microfilaments on Ca 2ϩ sequestration by the endoplasmic reticulum or on store-operated currents in ␤-cells as in other cells (21,25,36).…”

Section: Impact Of Actin Depolymerization On Metabolic Amplification mentioning

confidence: 67%

Metabolic amplifying pathway increases both phases of insulin secretion independently of β-cell actin microfilaments

Mourad¹,

Nenquin²,

Henquin³

2010

American Journal of Physiology-Cell Physiology

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]c was elevated and controlled by KCl or tolbutamide, the amplifying action of glucose was facilitated by actin depolymerization and unaffected by polymerization. Both phases of IS were larger in response to high-glucose than to tolbutamide in low-glucose, although triggering [Ca 2ϩ ]c was lower. This difference in IS, due to amplification, persisted when the IS rate was doubled by actin depolymerization or polymerization. In conclusion, metabolic amplification is rapid and influences the first as well as the second phase of IS. It is a late step of stimulus-secretion coupling, which does not require functional actin microfilaments and could correspond to acceleration of the priming process conferring release competence to insulin granules. biphasic insulin release; cytosolic calcium; exocytosis; insulin granules; pancreatic islets THE RATE OF INSULIN SECRETION by pancreatic ␤-cells is controlled by a hierarchical interaction among circulating nutrients, hormones, and neurotransmitters. The preeminent influence of glucose itself is exerted via two signaling pathways that both require metabolism of the sugar in ␤-cells (1, 11, 39). In the triggering pathway, closure of ATP-sensitive potassium (K ATP ) channels by adenine nucleotides permits membrane depolarization, which leads to Ca 2ϩ influx through voltagegated calcium channels and results in an increase in the cytosolic free Ca 2ϩ concentration ([Ca 2ϩ ] c ) that eventually triggers exocytosis of insulin granules. Simultaneously, glucose activates a metabolic amplifying pathway that does not involve additional action on K ATP channels or further rise in [Ca 2ϩ ] c but that augments the secretory response to the triggering Ca 2ϩ signal (14). The cellular mechanisms and effectors of this amplification have not yet been identified.During a hyperglycemic clamp, the increase in plasma insulin concentration is biphasic in humans (4) and rodents (13,29). In vitro, when a perfused pancreas or perifused isolated islets are challenged by an abrupt and steady increase in the glucose concentration, the acceleration of insulin secretion follows a biphasic pattern with a prominent rapid first phase and a sustained second phase (6,12,13,39,54). The mechanisms underlying the biphasic kinetics of insulin secretion are incompletely elucidated and probably involve both the time course of intracellular signals and the distribution of insulin granules in distinct pools (12,27,30,35,41,50). The first phase is commonly attributed to Ca 2ϩ -induced exocytosis of insulin granules from a limited pool of docked (tethered to the plasma membrane) and primed (release competent) granules. In contrast, the second phase is thought to involve functional recruitment or physical translocation of granules to the exocytotic sites. The characteristics and localization of this or these reserve pool(s) are still disputed (3,16,19,31,35,38). However, the general view holds that the amplifying action of glucose is necessary for the second phase but not involved in the first phase.Most actin micro...

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Section: Impact Of Actin Depolymerization On Metabolic Amplification mentioning

confidence: 67%

Metabolic amplifying pathway increases both phases of insulin secretion independently of β-cell actin microfilaments

Mourad¹,

Nenquin²,

Henquin³

2010

American Journal of Physiology-Cell Physiology

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“…However, AnxA6 co-localizes with actin, particularly in membrane ruffles of fibroblasts (30,66). Furthermore, we showed that constitutive membrane localization of AnxA6 caused a rearrangement of F-actin at the plasma membrane, indicating that AnxA6 stabilizes the cortical cytoskeleton (67). Interestingly, in these studies membrane-anchored AnxA6, but not AnxA1 or AnxA2, via interaction with the actin cytoskeleton, inhibited store-operated Ca 21 -entry (SOCE) (67).…”

Section: Anxa6 Interacts With Cytoskeleton Componentsmentioning

confidence: 72%

“…Interestingly, in these studies membrane-anchored AnxA6, but not AnxA1 or AnxA2, via interaction with the actin cytoskeleton, inhibited store-operated Ca 21 -entry (SOCE) (67). Latrunculin A abolished the inhibitory effect of membrane-anchored AnxA6 on SOCE, further implicating that AnxA6 is a key player that links the actin cytoskeleton with the activity of transmembrane proteins (67).…”

Section: Anxa6 Interacts With Cytoskeleton Componentsmentioning

confidence: 88%

Annexin A6 is an organizer of membrane microdomains to regulate receptor localization and signalling

et al. 2011

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Annexin A6 (AnxA6) belongs to the conserved annexin protein family—a group of Ca2+‐dependent membrane binding proteins. It is the largest of all annexin proteins and upon activation, binds to negatively charged phospholipids in the plasma membrane and endosomes. In addition, AnxA6 associates with cholesterol‐rich membrane microdomains termed lipid rafts. Membrane cholesterol triggers Ca2+‐independent translocation of AnxA6 to membranes and AnxA6 levels determine the number of caveolae, a form of specialized rafts at the cell surface. AnxA6 also has an F‐actin binding domain and interacts with cytoskeleton components. Taken together, this suggests that AnxA6 has a scaffold function to link membrane microdomains with the organization of the cytoskeleton. Such a link facilitates AnxA6 to participate in plasma membrane repair and it would also impact on receptor signalling at the cell surface, growth factor, and lipoprotein receptor trafficking, Ca2+‐channel activity and T cell activation. Hence, the regulation of cell surface receptors by AnxA6 may be facilitated by its unique structure that allows recruitment of interaction partners and simultaneously bridging specialized membrane domains with cortical actin surrounding activated receptors. © 2011 IUBMB IUBMB Life, 63(11): 1009–1017, 2011

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“…Thus, cytosolic AnxA6 is probably translocated to distinct subcellular membrane locations upon virus infection, due to the dysregulation of Ca 2ϩ homeostasis observed after IAV infection (24,58). If AnxA6 is overexpressed and targeted at the plasma membrane, it has been shown that it interacts with, recruits, and causes the rearrangement of F-actin, resulting in stabilization of the cortical cytoskeleton (40). In the present study, we have demonstrated that M2 physically interacts with AnxA6 in infected cells and colocalizes with AnxA6-GFP at the plasma membrane of infected cells ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Human Annexin A6 Interacts with Influenza A Virus Protein M2 and Negatively Modulates Infection

Kien

Manière

et al. 2012

J Virol

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The influenza A virus M2 ion channel protein has the longest cytoplasmic tail (CT) among the three viral envelope proteins and is well conserved between different viral strains. It is accessible to the host cellular machinery after fusion with the endosomal membrane and during the trafficking, assembly, and budding processes. We hypothesized that identification of host cellular interactants of M2 CT could help us to better understand the molecular mechanisms regulating the M2-dependent stages of the virus life cycle. Using yeast two-hybrid screening with M2 CT as bait, a novel interaction with the human annexin A6 (AnxA6) protein was identified, and their physical interaction was confirmed by coimmunoprecipitation assay and a colocalization study of virus-infected human cells. We found that small interfering RNA (siRNA)-mediated knockdown of AnxA6 expression significantly increased virus production, while its overexpression could reduce the titer of virus progeny, suggesting a negative regulatory role for AnxA6 during influenza A virus infection. Further characterization revealed that AnxA6 depletion or overexpression had no effect on the early stages of the virus life cycle or on viral RNA replication but impaired the release of progeny virus, as suggested by delayed or defective budding events observed at the plasma membrane of virus-infected cells by transmission electron microscopy. Collectively, this work identifies AnxA6 as a novel cellular regulator that targets and impairs the virus budding and release stages of the influenza A virus life cycle. Influenza A virus (IAV) is an enveloped virus with a segmented negative-sense RNA genome. The eight RNA segments encode 11 proteins (44). Influenza virus is pleomorphic (23), forming spherical virions that are ϳ100 nm in diameter as well as filamentous virions that are ϳ100 nm in diameter and over 20 m in length. The viral lipid envelope, derived by budding from the apical plasma membrane of the host cell, contains two major envelope glycoproteins, the receptor-binding/membrane fusion protein hemagglutinin (HA) and the enzyme neuraminidase (NA). A third minor (ϳ16 to 20 molecules/virion) integral membrane protein, M2, is a proton-selective ion channel that allows virion interior acidification for efficient uncoating after fusion in endosomes. M2 contains 97 amino acid residues and assembles into a homotetramer. This small type III integral membrane protein contains a single 19-residue transmembrane domain that forms the pore of the ion channel, a short (24-residue) amino-terminal ectodomain, and a long (54-residue) carboxy-terminal cytoplasmic domain (27,34,45). This cytoplasmic tail (CT) is highly conserved among viral strains (57).In the early stages of the replication cycle, after virus internalization by endocytosis, endosomal acidification activates M2 ion channel activity, causing acidification of the virus interior and leading to dissociation of the matrix protein M1 from the viral ribonucleoprotein (vRNP) complex (reviewed in reference 47). M2 is the targ...

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Plasma Membrane-associated Annexin A6 Reduces Ca2+ Entry by Stabilizing the Cortical Actin Cytoskeleton

Cited by 65 publications

References 57 publications

Metabolic amplifying pathway increases both phases of insulin secretion independently of β-cell actin microfilaments

Metabolic amplifying pathway increases both phases of insulin secretion independently of β-cell actin microfilaments

Annexin A6 is an organizer of membrane microdomains to regulate receptor localization and signalling

Human Annexin A6 Interacts with Influenza A Virus Protein M2 and Negatively Modulates Infection

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