Binding of Vac14 to neuronal nitric oxide synthase: Characterisation of a new internal PDZ‐recognition motif

Lemaire, Jean-François; McPherson, Peter S.

doi:10.1016/j.febslet.2006.11.061

Cited by 31 publications

(22 citation statements)

References 31 publications

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“…No similar sequence is present at the C termini of the beta HPV E6s (Fig. 1A), but the range of sequences that bind to PDZ proteins is in fact much broader than had previously been appreciated (64), and there are four or more rather degenerate C-terminal PDZ binding sequences as well as internal PDZ binding sequences (39). It is also possible that the interaction between beta E6s and these PDZ domain proteins is not mediated by a classical C-terminal interaction but rather by binding via a protein intermediate or by binding to another sequence in the PDZ protein.…”

Section: Discussionmentioning

confidence: 98%

Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

White

Kramer

Tan

et al. 2012

J Virol

183

240

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We have begun to define the human papillomavirus (HPV)-associated proteome for a subset of the more than 120 HPV types that have been identified to date. Our approach uses a mass spectrometry-based platform for the systematic identification of interactions between human papillomavirus and host cellular proteins, and here we report a proteomic analysis of the E6 proteins from 16 different HPV types. The viruses included represent high-risk, low-risk, and non-cancer-associated types from genus alpha as well as viruses from four different species in genus beta. The E6 interaction data set consists of 153 cellular proteins, including several previously reported HPV E6 interactors such as p53, E6AP, MAML1, and p300/CBP and proteins containing PDZ domains. We report the genus-specific binding of E6s to either E6AP or MAML1, define the specific HPV E6s that bind to p300, and demonstrate several new features of interactions involving beta HPV E6s. In particular, we report that several beta HPV E6s bind to proteins containing PDZ domains and that at least two beta HPV E6s bind to p53. Finally, we report the newly discovered interaction of proteins of E6 of beta genus, species 2, with the Ccr4-Not complex, the first report of a viral protein binding to this complex. This data set represents a comprehensive survey of E6 binding partners that provides a resource for the HPV field and will allow continued studies on the diverse biology of the human papillomaviruses.T he human papillomaviruses (HPVs) comprise more than 120 different virus types, each with a double-stranded DNA genome of approximately 8 kb. The HPVs have similar genome organizations, with regulatory functions encoded by the early (E) genes and structural components encoded by the late (L) genes (reviewed in reference 24). HPVs of different types differ in DNA sequences by 10% or more in the L1 gene, and the other viral genes exhibit a greater degree of sequence diversity between types (6, 15). Papillomaviruses are grouped into genera based on their L1 gene sequences and are further subdivided into species, with most of the HPVs in genus alpha or genus beta. The genus alpha HPVs infect the mucosal epithelium, and those that are the etiological agent responsible for the development of anogenital cancers (including cervical cancer) fall into genus alpha, species 7, and genus alpha, species 9. Beta-type HPVs infect the cutaneous epithelium.The HPV E6 protein has long been appreciated as a critical regulator of the viral life cycle and driver of tumorigenesis for the high-risk HPVs. Through the action of the HPV E7 protein, the G 1 -S checkpoint is bypassed in infected cells by the inactivation of the retinoblastoma tumor suppressor protein (pRB1) (17,18,46). This results in a cellular environment that is conducive to the replication of the viral DNA but in which proapoptotic signals have been triggered. One crucial function of high-risk HPV E6 proteins is to counteract the effects of p53 following this trigger, and this is accomplished by the targeted ubiquitylati...

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Section: Discussionmentioning

confidence: 98%

Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

White

Kramer

Tan

et al. 2012

J Virol

183

240

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“…Alternatively, PI(3,5)P 2 may play a critical role in an as yet unidentified neuronal-specific endosomally derived organelle. Indeed, during subcellular fractionation of rat brain, Vac14 was enriched in microsomal membranes from synapses (41).…”

Section: Discussionmentioning

confidence: 99%

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Zhang¹,

Zolov²,

Chow³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

196

256

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The signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), likely functions in multiple signaling pathways. Here, we report the characterization of a mouse mutant lacking Vac14, a regulator of PI(3,5)P 2 synthesis. The mutant mice exhibit massive neurodegeneration, particularly in the midbrain and in peripheral sensory neurons. Cell bodies of affected neurons are vacuolated, and apparently empty spaces are present in areas where neurons should be present. Similar vacuoles are found in cultured neurons and fibroblasts. Selective membrane trafficking pathways, especially endosome-to-TGN retrograde trafficking, are defective. This report, along with a recent report on a mouse with a null mutation in Fig4, presents the unexpected finding that the housekeeping lipid, PI(3,5)P 2, is critical for the survival of neural cells.T he low-abundance signaling lipids, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ) and phosphatidylinositol 5-phosphate (PI(5)P), were discovered relatively recently (1-3). Because of their low abundance and the limited number of tools available for their study, relatively little is known about these lipids.An interesting property of PI(3,5)P 2 occurs in yeast, where a stimulus of hyperosmotic shock induces dramatic and transient changes in the levels of PI(3,5)P 2 . The levels of PI(3,5)P 2 transiently rise Ͼ20-fold (4). Within 1 minute, the levels rise 5-fold; by 5 minutes, they increase Ͼ20-fold; there is a short plateau of 10 min, and then PI(3,5)P 2 levels decrease at a rate similar to their increase. The rapid decrease in PI(3,5)P 2 levels occurs even though the cells remain in hyperosmotic media. Vacuole volume undergoes transient changes that parallel PI(3,5)P 2 levels. That these rapid and transient changes occur even in the presence of a sustained stimulus strongly suggests that PI(3,5)P 2 plays a major role in signaling pathways related to adaptation.Several proteins are required for the synthesis and turnover of PI(3,5)P 2 . PI(3,5)P 2 is synthesized from PI(3)P by the PI(3)P 5-kinase Fab1/PIKfyve/PIP5K3 (5, 6). Fab1 is stimulated by a regulatory complex that contains Vac14 (7, 8) and Fig4 (4, 9). Surprisingly, the Vac14/Fig4 complex plays two opposing roles in the regulation of steady-state levels of PI(3,5)P 2 . Vac14/Fig4 both activate Fab1 and also function in the breakdown of PI(3,5)P 2 through the lipid phosphatase activity of Fig4 (4, 9-11).In mammals, generation of PI(3,5)P 2 is predicted to impact PI(5)P production. In vitro studies have shown that PI(5)P can be generated from PI(3,5)P 2 through the PI(3,5)P 2 3-phosphatase activity of members of the myotubularin family and related proteins including MTM1, MTMR1, MTMR2, MTMR3, MTMR6, and hJUMPY/MTMR14 (12-15). In addition, PIKfyve/Fab1 can generate both PI(3,5)P 2 and PI(5)P in vitro (16). The source of PI(5)P in vivo has not been established. However, the generation of PI(5)P from either pathway requires PIKfyve/ Fab1 activity, either to produce the substrate for myotubularin [PI(3,5)P 2 ] or to produce PI(5...

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“…Interactions with other members of the PIKfyve protein complex may also be important for activation of PIKfyve at synapses. For example, Vac14 has a motif that interacts with PDZ domains (82), which are highly abundant protein interaction domains found in many scaffolding proteins in the postsynaptic density.…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent PI(3,5)P ₂ synthesis controls AMPA receptor trafficking during synaptic depression

McCartney

Zolov²,

Kauffman³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Dynamic regulation of phosphoinositide lipids (PIPs) is crucial for diverse cellular functions, and, in neurons, PIPs regulate membrane trafficking events that control synapse function. Neurons are particularly sensitive to the levels of the low abundant PIP, phosphatidylinositol 3,5-bisphosphate [PI(3,5)P 2 ], because mutations in PI(3,5)P 2 -related genes are implicated in multiple neurological disorders, including epilepsy, severe neuropathy, and neurodegeneration. Despite the importance of PI(3,5)P 2 for neural function, surprisingly little is known about this signaling lipid in neurons, or any cell type. Notably, the mammalian homolog of yeast vacuole segregation mutant (Vac14), a scaffold for the PI(3,5)P 2 synthesis complex, is concentrated at excitatory synapses, suggesting a potential role for PI(3,5)P 2 in controlling synapse function and/or plasticity. PI(3,5)P 2 is generated from phosphatidylinositol 3-phosphate (PI3P) by the lipid kinase PI3P 5-kinase (PIKfyve). Here, we present methods to measure and control PI(3,5)P 2 synthesis in hippocampal neurons and show that changes in neural activity dynamically regulate the levels of multiple PIPs, with PI(3,5)P 2 being among the most dynamic. The levels of PI(3,5)P 2 in neurons increased during two distinct forms of synaptic depression, and inhibition of PIKfyve activity prevented or reversed induction of synaptic weakening. Moreover, altering neuronal PI(3,5)P 2 levels was sufficient to regulate synaptic strength bidirectionally, with enhanced synaptic function accompanying loss of PI(3,5)P 2 and reduced synaptic strength following increased PI(3,5)P 2 levels. Finally, inhibiting PI(3,5)P 2 synthesis alters endocytosis and recycling of AMPA-type glutamate receptors (AMPARs), implicating PI(3,5)P 2 dynamics in AMPAR trafficking. Together, these data identify PI(3,5)P 2 -dependent signaling as a regulatory pathway that is critical for activity-dependent changes in synapse strength.PIKfyve | Fab1 | phosphatidylinositol lipids | synaptic plasticity | Vac14 P hosphorylated phosphoinositide lipids (PIPs) regulate diverse cellular processes (reviewed in refs. 1, 2). These seven interconvertible PIP species are synthesized and turned over by highly regulated lipid kinases and phosphatases. PIPs likely assemble complex protein machines on membrane subdomains through binding of specific downstream protein effectors, which provides tight spatial and temporal control of cellular processes. Such precision is likely critical for complex cellular functions, including regulation of synaptic strength in the CNS.Pleiotropic defects are associated with impairments in phosphatidylinositol 3,5-bisphosphate [PI(3,5)P 2 ] synthesis (reviewed in ref.3). Mutations in FIG4, the gene that encodes a positive regulator of PI(3,5)P 2 (4-10), are linked to several neurological disorders, including Charcot-Marie-Tooth type 4J (CMT4J) (4, 11), ALS, and primary lateral sclerosis (12), familial epilepsy with polymicrogyria (13) and Yunis-Varón syndrome (14). Little is known about how pert...

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Binding of Vac14 to neuronal nitric oxide synthase: Characterisation of a new internal PDZ‐recognition motif

Cited by 31 publications

References 31 publications

Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Activity-dependent PI(3,5)P ₂ synthesis controls AMPA receptor trafficking during synaptic depression

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Binding of Vac14 to neuronal nitric oxide synthase: Characterisation of a new internal PDZ‐recognition motif

Cited by 31 publications

References 31 publications

Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

Comprehensive Analysis of Host Cellular Interactions with Human Papillomavirus E6 Proteins Identifies New E6 Binding Partners and Reflects Viral Diversity

Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Activity-dependent PI(3,5)P 2 synthesis controls AMPA receptor trafficking during synaptic depression

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Product

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Activity-dependent PI(3,5)P ₂ synthesis controls AMPA receptor trafficking during synaptic depression