VAMP-associated Proteins (VAP) as Receptors That Couple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Proteostasis with Lipid Homeostasis

Ernst, Wayne L.; Shome, Kuntala; Wu, Christine C.; Gong, Xiaowei; Frizzell, Raymond A.; Aridor, Meir

doi:10.1074/jbc.m115.692749

Cited by 32 publications

(38 citation statements)

References 82 publications

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“…For the latter, an extra binding site in VAP has been discovered: two partially conserved acidic residues in a loop at some distance from the main FFAT binding site of VAP partly mediate binding by the FFAT--like motif of FAF1, a ubiquitin--binding adaptor ( Fig. 1A) [43] . This finding suggests that multiple elements in VAP modulate overall affinity for binding partners.…”

Section: Cytoplasmic Interactors Of Vap Carry Out Diverse Functions Bmentioning

confidence: 99%

“…A further, weaker dimerization occurs between two FFAT motifs that are both binding VAP [16] . Thus, a dimeric protein containing a low affinity variant FFAT--like motif can use the avidity of bivalent interaction with VAP dimers/oligomers to target the ER quite tightly [30,43] . VAP interacts not only with itself, but also with other integral ER membrane proteins.…”

Section: Interactions Within the Ermentioning

confidence: 99%

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VAP, a Versatile Access Point for the Endoplasmic Reticulum: Review and analysis of FFAT-like motifs in the VAPome

Murphy¹,

Levine²

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

270

413

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Dysfunction of VAMP-associated protein (VAP) is associated with neurodegeneration, both Amyotrophic Lateral Sclerosis and Parkinson's disease. Here we summarize what is known about the intracellular interactions of VAP in humans and model organisms. VAP is a simple, small and highly conserved protein on the cytoplasmic face of the endoplasmic reticulum (ER). It is the sole protein on that large organelle that acts as a receptor for cytoplasmic proteins. This may explain the extremely wide range of interacting partners of VAP, with components of many cellular pathways binding it to access the ER. Many proteins that bind VAP also target other intracellular membranes, so VAP is a component of multiple molecular bridges at membrane contact sites between the ER and other organelles. So far approximately 100 proteins have been identified in the VAP interactome (VAPome), of which a small minority have a "two phenylalanines in an acidic tract" (FFAT) motif as it was originally defined. We have analyzed the entire VAPome in humans and yeast using a simple algorithm that identifies many more FFAT-like motifs. We show that approximately 50% of the VAPome binds directly or indirectly via the VAP-FFAT interaction. We also review evidence on pathogenesis in genetic disorders of VAP, which appear to arise from reduced overall VAP levels, leading to ER stress. It is not possible to identify one single interaction that underlies disease. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.

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Section: Cytoplasmic Interactors Of Vap Carry Out Diverse Functions Bmentioning

confidence: 99%

Section: Interactions Within the Ermentioning

confidence: 99%

VAP, a Versatile Access Point for the Endoplasmic Reticulum: Review and analysis of FFAT-like motifs in the VAPome

Murphy¹,

Levine²

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

270

413

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“…To elucidate the mechanisms underlying CFTR malfunction, its cellular itinerary has been studied rigorously. [63][64][65][66][67][68] Nascent CFTR becomes core-glycosylated (135 kDa) in the endoplasmic reticulum and is further modified to become fully complex-glycosylated (180 kDa) as it moves through the trans-Golgi network before reaching its functional destination at the plasma membrane. The most common CFTR mutation features a complete deletion of the phenylalanine at position 508 (F508del).…”

Section: Exogenous Cmcftr Translates and Localizes To The Plasma Membmentioning

confidence: 99%

Lipid Nanoparticle-Delivered Chemically Modified mRNA Restores Chloride Secretion in Cystic Fibrosis

et al. 2018

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The promise of gene therapy for the treatment of cystic fibrosis has yet to be fully clinically realized despite years of effort toward correcting the underlying genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR). mRNA therapy via nanoparticle delivery represents a powerful technology for the transfer of genetic material to cells with large, widespread populations, such as airway epithelia. We deployed a clinically relevant lipid-based nanoparticle (LNP) for packaging and delivery of large chemically modified CFTR mRNA (cmCFTR) to patient-derived bronchial epithelial cells, resulting in an increase in membrane-localized CFTR and rescue of its primary function as a chloride channel. Furthermore, nasal application of LNP-cmCFTR restored CFTR-mediated chloride secretion to conductive airway epithelia in CFTR knockout mice for at least 14 days. On day 3 post-transfection, CFTR activity peaked, recovering up to 55% of the net chloride efflux characteristic of healthy mice. This magnitude of response is superior to liposomal CFTR DNA delivery and is comparable with outcomes observed in the currently approved drug ivacaftor. LNP-cmRNA-based systems represent a powerful platform technology for correction of cystic fibrosis and other monogenic disorders.

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“…Bap31 and a VCP mutant (K524M) have been shown to interact to exert a dominant negative effect on retrotranslocation and cause proteins to accumulate at the juxtanuclear region [22]. VAMP-associated proteins (VAPs) inhibit the degradation of CFTR∆F508 through interactions with the RMA1-Derlin-Bap31-VCP pathway [30]. In our investigation of the mechanism by which Bap31 regulates VCP expression, we first observed that Bap31 regulates the mRNA and protein expression levels of VCP both in vitro and in vitro ( Fig.…”

Section: Discussionmentioning

confidence: 99%

B-Cell Receptor-Associated Protein 31 Regulates the Expression of Valosin-Containing Protein Through Elf2

Jia

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: B-cell receptor-associated protein 31 (Bap31) is an evolutionarily conserved, ubiquitously expressed, polytopic integral membrane protein in the endoplasmic reticulum (ER) that is involved in the regulation of apoptosis, protein transport and degradation. Patients with Bap31 mutations exhibit symptoms similar to those exhibited by patients with central nervous system (CNS) diseases, such as deafness, dystonia, and intellectual disability. The present study aimed to investigate the function of Bap31 in CNS diseases by identifying a CNS disease-related gene regulated by Bap31 and exploring the underlying molecular mechanism. Methods: ShRNA-Bap31 and siRNA-Bap31 were used to knockdown Bap31 in N₂a cells, and real-time PCR was performed to detect the mRNA levels of genes involved in CNS diseases. Western blot analyses were used to examine the protein levels of the candidate gene (valosin-containing protein, VCP) both in vivo and in vitro. The functions of Bap31 and VCP in mediating the degradation of the hyper-unstable mutant of cystic fibrosis trans-membrane conductance regulator (CFTRΔF508) were studied. Moreover, real-time PCR, Western blot and dual luciferase reporter analyses were conducted to investigate the molecular mechanism by which Bap31 regulates the expression levels of VCP. Results: VCP was identified as a candidate gene based on its differential expression in N₂a cells following both shRNA- and siRNA-mediated knockdown of Bap31. Both the mRNA and protein levels of VCP were regulated by Bap31 in vivo and in vitro. In the ER-associated degradation (ERAD) pathway, Bap31 also regulated VCP expression and caused differences in the binding quantities of CFTRΔF508 and VCP. Furthermore, a transcription factor of VCP (E74-like factor 2, Elf2) was regulated by Bap31, and Elf2 mediated the changes in VCP transcription and expression in cells with altered Bap31 expression. Conclusion: These results indicate that Bap31 regulates the expression of VCP possibly via Elf2 and support the potential molecular function of Bap31 in CNS diseases.

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VAMP-associated Proteins (VAP) as Receptors That Couple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Proteostasis with Lipid Homeostasis

Cited by 32 publications

References 82 publications

VAP, a Versatile Access Point for the Endoplasmic Reticulum: Review and analysis of FFAT-like motifs in the VAPome

VAP, a Versatile Access Point for the Endoplasmic Reticulum: Review and analysis of FFAT-like motifs in the VAPome

Lipid Nanoparticle-Delivered Chemically Modified mRNA Restores Chloride Secretion in Cystic Fibrosis

B-Cell Receptor-Associated Protein 31 Regulates the Expression of Valosin-Containing Protein Through Elf2

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