VAP Proteins – From Organelle Tethers to Pathogenic Host Interactors and Their Role in Neuronal Disease

Kors, Suzan; Costello, Joseph L.; Schrader, Michael

doi:10.3389/fcell.2022.895856

Cited by 24 publications

(18 citation statements)

References 219 publications

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“…1a ) 1 , 5 , 6 . One well-established ERMCS tether is the ER-localized Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB) 13 – 15 , which interacts with mitochondrial binding partners to facilitate calcium and lipid transfer 16 , 17 and can harbour mutations that cause a severe form of motor neuron disease 18 , 19 . The best characterized binding partner for VAPB in the mitochondria is the outer mitochondrial membrane (OMM) component, protein tyrosine phosphatase interacting protein 51 (PTPIP51) 14 , 16 , 20 .…”

Section: Mainmentioning

confidence: 99%

Motion of VAPB molecules reveals ER–mitochondria contact site subdomains

Obara,

Nixon-Abell,

Moore

et al. 2024

Nature

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To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle–organelle contact sites1,2. Endoplasmic reticulum–mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites3,4. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle5,6. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation7,8, a clear understanding of their nanoscale organization and regulation is still lacking. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis.

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Section: Mainmentioning

confidence: 99%

Motion of VAPB molecules reveals ER–mitochondria contact site subdomains

Obara,

Nixon-Abell,

Moore

et al. 2024

Nature

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“…The increased appreciation of interorganelle interactions in recent years has unveiled a variety of MCSs in eukaryotes 39 . These closely apposed and tethered membranes facilitate numerous cellular processes, making them prime candidates for microbial control or mimicry 9,10 . Thus far, examples of pathogenic subversion of MCSs have been limited to interactions between eukaryotic membrane compartments [4][5][6] .…”

Section: Discussionmentioning

confidence: 99%

“…Recent research indicates that ER-mediated MCSs are susceptible to pathogen subversion 9,10 . Pathogens appear to either manipulate pre-existing MCSs 4 or establish new ones between the ER and the host-derived membrane that harbors the pathogen 6 .…”

Section: Introductionmentioning

confidence: 99%

An obligate intracellular bacterial pathogen forms a direct, interkingdom membrane contact site

Acevedo-Sánchez

Woida

Kräemer

et al. 2023

Preprint

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Interorganelle communication regulates cellular homeostasis through the formation of tightly-associated membrane contact sites 1,3. Prior work has identified several ways that intracellular pathogens alter contacts between eukaryotic membranes 4,6, but there is no existing evidence for contact sites spanning eukaryotic and prokaryotic membranes. Here, using a combination of live-cell microscopy and transmission and focused-ion-beam scanning electron microscopy, we demonstrate that the intracellular bacterial pathogenRickettsia parkeriforms a direct membrane contact site between its bacterial outer membrane and the rough endoplasmic reticulum (ER), with tethers that are approximately 55 nm apart. Depletion of the ER-specific tethers VAPA and VAPB reduced the frequency of rickettsia-ER contacts, suggesting these interactions mimic organelle-ER contacts. Overall, our findings illuminate a direct, interkingdom membrane contact site uniquely mediated by rickettsia that seems to mimic traditional host MCSs.

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“…Pathogens employ intricate strategies to co-opt host cell machinery and manipulate cellular metabolism to ensure their survival and replication. Recent studies have revealed the pathogen’s ability to modify host inter-organelle communication (Kors et al, 2022; Jiang et al, 2022). Upon host cell entry, certain obligate intracellular bacteria adopt a unique endocytic membrane-bound vacuole, referred to as the Bacteria-Containing Vacuole (BCV), to evade the host immune response and support bacterial replication (Santos and Enninga, 2016; Petit and Lebreton, 2022).…”

Section: Introductionmentioning

confidence: 99%

The novel bacterial effector proteinCbEPF1 mediates ER-LD membrane contacts to regulate host lipid droplet metabolism

Angara,

Sadi,

Gilk

2023

Preprint

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Effective intracellular communication between cellular organelles is pivotal for maintaining cellular homeostasis. Tether proteins, which are responsible for establishing membrane contact sites between cell organelles, enable direct communication between organelles and ultimately influence organelle function and host cell homeostasis. While recent research has identified tether proteins in several bacterial pathogens, their functions have predominantly been associated with mediating inter-organelle communication specifically between the bacteria containing vacuole (BCV) and the host endoplasmic reticulum (ER). However, this study reveals a novel bacterial effector protein,CbEPF1, which acts as a molecular tether beyond the confines of the BCV and facilitates interactions between host cell organelles.Coxiella burnetii, an obligate intracellular bacterial pathogen, encodes the FFAT motif-containing proteinCbEPF1 which localizes to host lipid droplets (LDs).CbEPF1 establishes inter-organelle contact sites between host LDs and the ER through its interactions with VAP family proteins. Intriguingly,CbEPF1 modulates growth of host LDs in a FFAT motif-dependent manner. These findings highlight the potential for bacterial effector proteins to impact host cellular homeostasis by manipulating inter-organelle communication beyond conventional BCVs.

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VAP Proteins – From Organelle Tethers to Pathogenic Host Interactors and Their Role in Neuronal Disease

Cited by 24 publications

References 219 publications

Motion of VAPB molecules reveals ER–mitochondria contact site subdomains

Motion of VAPB molecules reveals ER–mitochondria contact site subdomains

An obligate intracellular bacterial pathogen forms a direct, interkingdom membrane contact site

The novel bacterial effector proteinCbEPF1 mediates ER-LD membrane contacts to regulate host lipid droplet metabolism

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