FFAT rescues VAPA-mediated inhibition of ER-to-Golgi transport and VAPB-mediated ER aggregation

Prosser, Derek C.; Tran, Duvinh; Gougeon, Pierre‐Yves; Verly, Carine; Ngsee, Johnny K.

doi:10.1242/jcs.028696

Cited by 66 publications

(78 citation statements)

References 35 publications

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“…1A-C). The vacuole-like structures probably correspond to the dilated membranes viewed under light microscopy in cells expressing mutant VAPB (Kanekura et al, 2006;Teuling et al, 2007;Prosser et al, 2008). Interestingly, ,75% of these cells also showed a prominent nuclear envelope defect characterized by separation of the INM and ONM at discrete regions (Fig.…”

Section: Vapb-p56s Causes Swelling Of the Nuclear Envelopementioning

confidence: 90%

“…Expression plasmids, cell culture and transfection FLAG-tagged VAPB and Myc-tagged FFAT constructs were as described previously (Prosser et al, 2008). Gp210-GFP and Nup214-GFP were from EUROSCARF.…”

Section: Methodsmentioning

confidence: 99%

“…Familial ALS8 is caused by a P56S mutation in the vesicleassociated membrane protein-associated protein B and C (VAPB) gene (Nishimura et al, 2004;Chen et al, 2010). Overexpression of the VAPB P56S mutant protein leads to formation of large endoplasmic reticulum (ER)-derived membranes (Nishimura et al, 2004;Kanekura et al, 2006;Teuling et al, 2007;Prosser et al, 2008;Suzuki et al, 2009). VAPB is an integral membrane protein with an N-terminal major sperm protein (MSP) domain and a C-terminal transmembrane domain.…”

Section: Introductionmentioning

confidence: 99%

“…Replacement of P56 with a serine residue exposes a hydrophobic patch (Furuita et al, 2010;Kim et al, 2010) that renders the protein highly prone to aggregation (Kanekura et al, 2006). We have previously shown that cooverexpression of an FFAT-containing fragment, but not when the phenylalanine residues were replaced with alanine residues (named AAAT), rescued the abnormal ER morphology induced by mutant VAPB (Prosser et al, 2008). Here, we report that VAPB P56S mutation also causes a nuclear envelope defect characterized by separation of the outer and inner nuclear membrane (ONM and INM, respectively).…”

Section: Introductionmentioning

confidence: 99%

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Amyotrophic Lateral Sclerosis Mutant VAPB Causes a Nuclear Envelope Defect

Tran

Chalhoub

Schooley

et al. 2012

Journal of Cell Science

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SummaryA proline to serine mutation (P56S) in vesicle-associated membrane protein-associated protein B and C (VAPB) causes an autosomal dominant form of amyotrophic lateral sclerosis (ALS). We show that the mutation also causes a nuclear envelope defect. Transport of nucleoporins (Nups) and emerin (EMD) to the nuclear envelope is blocked, resulting in their sequestration in dilated cytoplasmic membranes. Simultaneous overexpression of the FFAT motif (two phenylalanine residues in an acidic track) antagonizes the effect of mutant VAPB and restores transport to the nuclear envelope. VAPB function is required for transport to the nuclear envelope, with knockdown of endogenous VAPB recapitulating this phenotype. Moreover, we identified the compartment into which the Nups and EMD were sequestered as the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), with nuclear envelope membrane proteins transiting to the ERGIC before VAPB-dependent retrograde transport to the nuclear envelope.

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Section: Vapb-p56s Causes Swelling Of the Nuclear Envelopementioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Amyotrophic Lateral Sclerosis Mutant VAPB Causes a Nuclear Envelope Defect

Tran

Chalhoub

Schooley

et al. 2012

Journal of Cell Science

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“…These results suggest that the expression of VAP-C may participate in the determination of tissue tropism of HCV propagation. aggregations of ER in culture cells and to sequester the wildtype protein into ubiquitinated inclusions (29,37). To examine the effects on the replication of HCV of the P56S mutation in VAPs, FLAG-tagged VAP mutants were expressed in the HCV replicon cells.…”

Section: Vap-c Impairs Hcv Propagationmentioning

confidence: 99%

Human VAP-C Negatively Regulates Hepatitis C Virus Propagation

Kukihara

Moriishi

Taguwa

et al. 2009

J Virol

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Human vesicle-associated membrane protein-associated protein (VAP) subtype A (VAP-AHepatitis C virus (HCV) is a major causative agent of chronic liver disease and thus a major public health problem, infecting at least 3% of the world population (47). HCV infection proceeds to the persistent stage in approximately 80% of patients, leading to the development of cirrhosis in 20% to 50% of patients, of whom approximately 5% eventually develop hepatocellular carcinoma (12). HCV encompasses a single-stranded positive-sense RNA genome of approximately 9.6 kb, which encodes a large precursor polyprotein comprising approximately 3,000 amino acids (26). The structural proteins are cleaved from the N-terminal one-fourth of the polyprotein by the host signal peptidase and signal peptide peptidase (23,32,33), resulting in the maturation of the capsid protein, two envelope proteins and viroporin p7. The NS2 protease cleaves after the carboxyl terminus, and then NS3 cleaves the appropriate downstream positions to produce NS4A, NS4B, NS5A, and NS5B (8, 42), all of which form the replication complex along with several host proteins (5, 21). NS5B is the RNAdependent RNA polymerase, which is a main enzymatic component of the replication complex of HCV (3), while NS5A is a membrane-anchored zinc-binding phosphoprotein that appears to possess diverse functions, including the suppression of host defense and the regulation of the virus's replication (1,4,6,41), although its biological function remains unclear.The NS5A protein has been shown to interact with several host proteins, including vesicle-associated membrane protein (VAMP)-associated protein (VAP) subtype A (VAP-A) (44) and subtype B (VAP-B) (9), FKBP8 (34), MyD88 (1), FBL2 (46), human butyrate-induced transcript 1 (hB-ind1) (40), and so on (25). VAP-A and VAP-B also bind to NS5B, although it remains unclear whether these interactions modulate HCV replication positively or negatively (9, 44). VAP-A and VAP-B have been shown to associate with the cytoplasmic face of the endoplasmic reticulum (ER) and the Golgi apparatus (38) and to consist of the major sperm protein (MSP) domain, the coiled-coil domain, and the transmembrane (TM) region, in that order (30,39), as shown in Fig. 1A. VAP was originally reported as a protein binding to VAMP, which is a synaptic vesicle SNARE protein required for synaptic-vesicle fusion in the nematode Aplysia californica, and was designated the 33-kDa VAMP-associated protein, VAP-33 (39). Two mammalian homologues, VAP-A and VAP-B, were subsequently identified (30,38). The transcription of VAP-A and VAP-B is ubiquitously detected in mammalian organs, including the heart, placenta, lung, liver, skeletal muscle, and pancreas (30), suggesting that VAP family proteins are involved in diverse cellular functions other than neurotransmitter release (30,38,49). Several VAP-interacting proteins share the FFAT motif (two phenylalanines in an acidic tract), which has the consensus amino acid sequence EFFDAXE, as determined by a comparison among oxysterol bind...

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Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

Tian,

Andrews,

Yan

et al. 2024

Chronic Diseases and Translational Medicine

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Calcium‐sensing receptor (CaSR), a family C G‐protein‐coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L‐Trp and L‐Phe), small peptides, anions (e.g., HCO3− and PO43−), and pH. CaSR‐mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein–protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+‐dependent cellular physiological processes and in CaSR‐dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G‐protein‐coupled receptors.

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FFAT rescues VAPA-mediated inhibition of ER-to-Golgi transport and VAPB-mediated ER aggregation

Cited by 66 publications

References 35 publications

Amyotrophic Lateral Sclerosis Mutant VAPB Causes a Nuclear Envelope Defect

Amyotrophic Lateral Sclerosis Mutant VAPB Causes a Nuclear Envelope Defect

Human VAP-C Negatively Regulates Hepatitis C Virus Propagation

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

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