VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis

Hua, Rong; Cheng, D.; Coyaud, Étienne; Freeman, Spencer A.; Pietro, Erminia Di; Wang, Yuqing; Vissa, Adriano; Yip, Christopher M.; Fairn, Gregory D.; Braverman, Nancy; Brumell, John H.; Trimble, William S.; Raught, Brian; Kim, Peter K.

doi:10.1083/jcb.201608128

Cited by 226 publications

(284 citation statements)

References 53 publications

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“…In addition the movement of peroxisomes was increased. Simultaneously the group of Peter Kim used a parallel approach to reach the same conclusions, additionally reporting that plasmalogen synthesis is impaired when the VAPB-ACBD5 tether is disrupted 31 . Recent studies have now identified patients carrying pathogenic mutations which lead to the loss of ACBD5 protein 32-34 .…”

Section: Resultsmentioning

confidence: 85%

Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations

et al. 2017

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Cooperation between cellular organelles such as mitochondria, peroxisomes and the ER is essential for a variety of important and diverse metabolic processes. Effective communication and metabolite exchange requires physical linkages between the organelles, predominantly in the form of organelle contact sites. At such contact sites organelle membranes are brought into close proximity by the action of molecular tethers, which often consist of specific protein pairs anchored in the membrane of the opposing organelles. Currently numerous tethering components have been identified which link the ER with multiple other organelles but knowledge of the factors linking the ER with peroxisomes is limited. Peroxisome-ER interplay is important because it is required for the biosynthesis of unsaturated fatty acids, ether-phospholipids and sterols with defects in these functions leading to severe diseases. Here, we characterize acyl-CoA binding domain protein 4 (ACBD4) as a tail-anchored peroxisomal membrane protein which interacts with the ER protein, vesicle-associated membrane protein-associated protein–B (VAPB) to promote peroxisome-ER associations.

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Section: Resultsmentioning

confidence: 85%

Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations

et al. 2017

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“…A separate region, comprising amino acids 71–81, serves as the ER‐to‐peroxisome targeting signal, as judged by the fact that the deletion of this sequence caused the PEX16(Δ66‐81)‐GFP to remain in the ER. PEX16 recruits multiple PMPs to the ER as shown for two TA PMPs (PEX26 and FIS1), as well as multi‐span PMPs (PMP34, PEX11β, and PEX10), a function that is conserved in plants . This recruitment depends on amino acids 66–103 in PEX16 and is independent of PEX3 and PEX19.…”

Section: Introductionmentioning

confidence: 88%

“…In mammals, the ER has the most abundant contact sites for peroxisomes (more than 90% of peroxisomes contact the ER) followed by mitochondria (~ 20%) and LDs (~ 20%) . Recently, two independent groups identified the tethers between the ER and peroxisomes in mammals (Fig B). The ER tethers are the vesicle‐associated membrane protein (VAMP)‐associated proteins (VAPs), which are implicated in tethering several different MCSs .…”

Section: Introductionmentioning

confidence: 99%

Peroxisome biogenesis, membrane contact sites, and quality control

et al. 2018

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Peroxisomes are conserved organelles of eukaryotic cells with important roles in cellular metabolism, human health, redox homeostasis, as well as intracellular metabolite transfer and signaling. We review here the current status of the different co‐existing modes of biogenesis of peroxisomal membrane proteins demonstrating the fascinating adaptability in their targeting and sorting pathways. While earlier studies focused on peroxisomes as autonomous organelles, the necessity of the ER and potentially even mitochondria as sources of peroxisomal membrane proteins and lipids has come to light in recent years. Additionally, the intimate physical juxtaposition of peroxisomes with other organelles has transitioned from being viewed as random encounters to a growing appreciation of the expanding roles of such inter‐organellar membrane contact sites in metabolic and regulatory functions. Peroxisomal quality control mechanisms have also come of age with a variety of mechanisms operating both during biogenesis and in the cellular response to environmental cues.

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“…The ER integral proteins VAPA and VAPB [vesicle-associated membrane protein-associated protein, referred to as VAPs here (8)] are common components of the MCS formed between the ER and various organelles (5,(9)(10)(11)(12)(13)(14). At each of these MCS, VAPs interact with different proteins that have a 7-aa sequence, known as a FFAT motif [two phenylalanines (FF) in an acidic tract (AT)] in common (15).…”

mentioning

confidence: 99%

IncV, a FFAT motif-containing Chlamydia protein, tethers the endoplasmic reticulum to the pathogen-containing vacuole

Stanhope

Flora

Bayne

et al. 2017

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

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Membrane contact sites (MCS) are zones of contact between the membranes of two organelles. At MCS, specific proteins tether the organelles in close proximity and mediate the nonvesicular trafficking of lipids and ions between the two organelles. The endoplasmic reticulum (ER) integral membrane protein VAP is a common component of MCS involved in both tethering and lipid transfer by binding directly to proteins containing a FFAT [two phenylalanines (FF) in an acidic tract (AT)] motif. In addition to maintaining cell homeostasis, MCS formation recently emerged as a mechanism by which intracellular pathogens hijack cellular resources and establish their replication niche. Here, we investigated the mechanism by which the Chlamydia-containing vacuole, termed the inclusion, establishes direct contact with the ER. We show that the Chlamydia protein IncV, which is inserted into the inclusion membrane, displays one canonical and one noncanonical FFAT motif that cooperatively mediated the interaction of IncV with VAP. IncV overexpression was sufficient to bring the ER in close proximity of IncV-containing membranes. Although IncV deletion partially decreased VAP association with the inclusion, it did not suppress the formation of ER-inclusion MCS, suggesting the existence of redundant mechanisms in MCS formation. We propose a model in which IncV acts as one of the primary tethers that contribute to the formation of ER-inclusion MCS. Our results highlight a previously unidentified mechanism of bacterial pathogenesis and support the notion that cooperation of two FFAT motifs may be a common feature of VAP-mediated MCS formation. Chlamydiahost cell interaction therefore constitutes a unique system to decipher the molecular mechanisms underlying MCS formation.endoplasmic reticulum-Chlamydia inclusion membrane contact sites | IncV | FFAT motif | VAP proteins | tether

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VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis

Cited by 226 publications

References 53 publications

Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations

Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations

Peroxisome biogenesis, membrane contact sites, and quality control

IncV, a FFAT motif-containing Chlamydia protein, tethers the endoplasmic reticulum to the pathogen-containing vacuole

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