Human VAPome Analysis Reveals MOSPD1 and MOSPD3 as Membrane Contact Site Proteins Interacting with FFAT-Related FFNT Motifs

Cabukusta, Birol; Berlin, Ilana; Elsland, Daphne M. van; Forkink, Iris; Spits, Menno; Jong, Anja W. M. de; Akkermans, Jimmy J.L.L.; Wijdeven, Ruud H.; Janssen, George M.C.; Veelen, Peter A. van; Neefjes, Jacques

doi:10.1016/j.celrep.2020.108475

Cited by 66 publications

(100 citation statements)

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“…The data also confirmed the presence of multiple types of contact sites between ER and lysosomes, possibly with different functions (Bonifacino & Neefjes, 2017;Fermie et al, 2018;Garrity et al, 2016;Lim et al, 2019). Numerous proteins involved in MCSs are currently being identified, and many studies focus on addressing the role of these proteins in spatial and temporal regulation of MCSs at the molecular level (Cabukusta et al, 2020;Huang et al, 2020;Lim et al, 2019). We believe our method, uniquely linking live-cell imaging of single organelles to ultrastructural detail, is promising to greatly accelerate understanding in temporal and structural regulation of MCSs at the system and molecular level.…”

Section: Discussionsupporting

confidence: 59%

Correlative Organelle Microscopy: fluorescence guided volume electron microscopy of intracellular processes

Loginov

Fermie

Fokkema

et al. 2021

Preprint

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Intracellular processes depend on a strict spatial and temporal organization of proteins and organelles. Directly linking molecular to nanoscale ultrastructural information is therefore crucial to understand cellular physiology. Volume or 3-dimensional (3D) correlative light and electron microscopy (volume-CLEM) holds unique potential to explore cellular physiology at high-resolution ultrastructural detail across cell volumes. Application of volume-CLEM is however hampered by limitations in throughput and 3D correlation efficiency. Addressing these limitations, we here describe a novel pipeline for volume-CLEM that provides high-precision (<100nm) registration between 3D fluorescence microscopy (FM) and 3D electron microscopy (EM) data sets with significantly increased throughput. Using multi-modal fiducial nanoparticles that remain fluorescent in epoxy resins and a 3D confocal fluorescence microscope integrated in a Focused Ion Beam Scanning Electron Microscope (FIB.SEM), our approach uses FM to target extremely small volumes of even single organelles for imaging in volume-EM, and obviates the need for post correlation of big 3D datasets. We extend our targeted volume-CLEM approach to include live-cell imaging, adding information on the motility of intracellular membranes selected for volume-CLEM. We demonstrate the power of our approach by targeted imaging of rare and transient contact sites between endoplasmic reticulum (ER) and lysosomes within hours rather than days. Our data suggest that extensive ER-lysosome and mitochondria-lysosome interactions restrict lysosome motility, highlighting the unique capabilities of our integrated CLEM pipeline for linking molecular dynamic data to high-resolution ultrastructural detail in 3D.

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Section: Discussionsupporting

confidence: 59%

Correlative Organelle Microscopy: fluorescence guided volume electron microscopy of intracellular processes

Loginov

Fermie

Fokkema

et al. 2021

Preprint

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“…Interestingly, overexpressed PDZD8 and Rab7 colocalize at the three-way junction of ER, endosomes, and mitochondria, thereby inducing the association of the endosome and mitochondria. Furthermore, a recent study indicates that PDZD8 participates in the VAP complex ( Cabukusta et al, 2020 ), which implies PDZD8’s roles in multiple different organelle contact sites. Since overexpression of MERCS proteins can disrupt their localization and therefore their functions, future studies will need to elucidate the location of endogenous PDZD8 among those contact sites.…”

Section: Mitochondria–endoplasmic Reticulum Contact Site Proteins At Other Organelle Contact Sitesmentioning

confidence: 99%

Endoplasmic Reticulum–Mitochondria Contact Sites—Emerging Intracellular Signaling Hubs

Aoyama-Ishiwatari

Hirabayashi

2021

Front. Cell Dev. Biol.

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It has become apparent that our textbook illustration of singular isolated organelles is obsolete. In reality, organelles form complex cooperative networks involving various types of organelles. Light microscopic and ultrastructural studies have revealed that mitochondria–endoplasmic reticulum (ER) contact sites (MERCSs) are abundant in various tissues and cell types. Indeed, MERCSs have been proposed to play critical roles in various biochemical and signaling functions such as Ca2+ homeostasis, lipid transfer, and regulation of organelle dynamics. While numerous proteins involved in these MERCS-dependent functions have been reported, how they coordinate and cooperate with each other has not yet been elucidated. In this review, we summarize the functions of mammalian proteins that localize at MERCSs and regulate their formation. We also discuss potential roles of the MERCS proteins in regulating multiple organelle contacts.

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“…The discovery of the third FFAT-motif-binding protein raised the question whether more motif-binding MSP domains are present in the human proteome. This led to the characterization of MOSPD1 and MOSPD3 with functional MSP domains ( Figure 1b ) ( Cabukusta et al, 2020 ). The MSP domains of MOSPD1 and MOSPD3 are diverged from the MSP domains of VAPA, VAPB and MOSPD2, which suggested that these domains might bind motifs different from FFAT ( Figure 2b ).…”

Section: Multiple Vaps and Ffat Motifsmentioning

confidence: 99%

“…The motifs MOSPD1 and MOSPD3 interact with could be predicted by the available FFAT motif search algorithm ( Slee and Levine,2019 ). Further analyses showed that the FFAT-related motifs favoured by MOSPD1 and MOSPD3 lack the acidic characteristics of FFAT but rather contain neutral amino acids and are thus called FFNT (two phenylalanines (FF) in a Neutral Tract) motifs ( Figure 1d ) ( Cabukusta et al, 2020 ).…”

Section: Multiple Vaps and Ffat Motifsmentioning

confidence: 99%

“…The role of VAPA and VAPB in forming contact sites is well appreciated and new interaction partners of VAPA and VAPB are unveiled each year ( Lindhout et al, 2019 ; Nthiga et al, 2020 ; Zhao et al, 2020 ; Inukai et al, 2021 ). Recent work from us and others unravelled three new human homologs of VAPA and VAPB, namely MOSPD1, MOSPD2, and MOSPD3, that also form MCS ( Di Mattia et al, 2018 ; Cabukusta et al, 2020 ). Along with an expanding VAP family, the number of motifs that can be recognized on target proteins also multiplied.…”

Section: Introductionmentioning

confidence: 99%

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What the VAP: The Expanded VAP Family of Proteins Interacting With FFAT and FFAT-Related Motifs for Interorganellar Contact

Neefjes

Cabukusta

2021

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Membrane contact sites are formed by tether proteins that have the ability to bring two organellar membranes together. VAP proteins are a family of endoplasmic reticulum (ER)-resident tether proteins specialized in interacting with FFAT (two phenylalanines in an acidic tract) peptide motifs in other proteins. If the FFAT-motif-containing proteins reside on other organelles, VAP proteins form contact sites between these organelles and the ER. The role of VAPA and VAPB, the two founding members of the VAP family in recruiting proteins to the ER and forming membrane contact sites is well appreciated as numerous interaction partners of VAPA and VAPB at different intracellular contact sites have been characterized. Recently, three new proteins -MOSPD1, MOSPD2 and MOSPD3- have been added to the VAP family. While MOSPD2 has a motif preference similar to VAPA and VAPB, MOSPD1 and MOSPD3 prefer to interact with proteins containing FFNT (two phenylalanines in a neutral tract) motifs. In this review, we discuss the recent advances in motif binding by VAP proteins along with the other biological processes VAP proteins are involved in.

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Human VAPome Analysis Reveals MOSPD1 and MOSPD3 as Membrane Contact Site Proteins Interacting with FFAT-Related FFNT Motifs

Cited by 66 publications

References 61 publications

Correlative Organelle Microscopy: fluorescence guided volume electron microscopy of intracellular processes

Correlative Organelle Microscopy: fluorescence guided volume electron microscopy of intracellular processes

Endoplasmic Reticulum–Mitochondria Contact Sites—Emerging Intracellular Signaling Hubs

What the VAP: The Expanded VAP Family of Proteins Interacting With FFAT and FFAT-Related Motifs for Interorganellar Contact

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