Making Contact: VAP Targeting by Intracellular Pathogens

Stanhope, Rebecca; Derré, Isabelle

doi:10.1177/2515256418775512

Cited by 8 publications

(4 citation statements)

References 12 publications

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“…As expected, knockdown of ATG12, a key macroautophagy conjugation protein, was associated with a significant decrease in the number of LC3B + bacteria ( Figure 5A ). We also examined a role for OSBPL binding partners VAPA and VAPB, proteins implicated in autophagosome biogenesis [ 40 ] and which are critical for the formation of pathogen-host membrane-contact sites [ 41 ]. A significant reduction in LC3B + Salmonella was observed when OSBPL7, OSBPL11, or VAPA were knocked down, suggesting OSBPL-VAPA interactions are required for recruitment of LC3B to Salmonella ( Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

Global Proximity Interactome of the Human Macroautophagy Pathway

Sydor

Coyaud

et al. 2021

Autophagy

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Macroautophagy is a highly conserved eukaryotic cellular pathway involving the engulfment of macromolecules, organelles, and invading microbes by a double-membrane compartment and subsequent lysosomal degradation. The mechanisms that regulate macroautophagy, and the interaction of its components with other cellular pathways, have remained unclear. Here, we performed proximity-dependent biotin identification (BioID) on 39 core human macroautophagy proteins, identifying over 700 unique high confidence proximity interactors with new putative connections between macroautophagic and essential cellular processes. Of note, we identify members of the OSBPL (oxysterol binding protein like) family as Atg8-family protein interactors. We subsequently conducted comprehensive screens of the OSBPL family for LC3B-binding and roles in xenophagy and aggrephagy. OSBPL7 and OSBPL11 emerged as novel lipid transfer proteins required for macroautophagy of selective cargo. Altogether, our proximity interaction map provides a valuable resource for the study of autophagy and highlights the critical role of membrane contact site proteins in the pathway.

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Section: Resultsmentioning

confidence: 99%

Global Proximity Interactome of the Human Macroautophagy Pathway

Sydor

Coyaud

et al. 2021

Autophagy

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“…The mechanistically best characterized case is Chlamydia trachomatis , which forms a replication-permissive compartment termed inclusion [77]. Intriguingly, the Chlamydia integral membrane proteins IncV and IncD tether the inclusion to the ER [78]. While IncV directly binds Vap on the ER through a FFAT motif [79], IncD indirectly makes contact to Vap through the FFAT motif-containing host protein CERT (ceramide transfer protein) [80, 81].…”

Section: Discussionmentioning

confidence: 99%

TheLegionella-driven PtdIns(4)Pgradient at LCV-ER membrane contact sites promotes Vap-, OSBP- and Sac1-dependent pathogen vacuole remodeling

Vormittag

Hüsler

Haneburger

et al. 2022

Preprint

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The causative agent of Legionnaires' disease, Legionella pneumophila, governs interactions with host cells by secreting ca. 330 different "effector" proteins. The facultative intracellular bacteria replicate in macrophages and amoeba within a unique compartment, the Legionella-containing vacuole (LCV). Hallmarks of LCV formation are the phosphoinositide (PI) lipid conversion from PtdIns(3)P to PtdIns(4)P, fusion with endoplasmic reticulum (ER)-derived vesicles and a tight association with the ER. Proteomics of purified LCVs revealed the presence of membrane contact sites (MCS) proteins implicated in lipid exchange. Using dually fluorescence-labeled Dictyostelium discoideum amoeba, we reveal that the VAMP-associated protein (Vap), the PtdIns(4)P 4-phosphatase Sac1, and the large fusion GTPase Sey1/atlastin-3 localize to the ER, but not to the LCV membrane, and that these ER-resident proteins promote intracellular replication of L. pneumophila and LCV remodeling. Moreover, oxysterol binding proteins (OSBPs) preferentially localize to the ER (OSBP8) or the LCV membrane (OSBP11), respectively, and promote (OSBP8) or restrict (OSBP11) intracellular replication of L. pneumophila and LCV expansion. Furthermore, the PtdIns(4)P-subverting L. pneumophila effectors LepB and SidC also promote LCV remodeling. Taken together, the Legionella- and host cell-driven PtdIns(4)P gradient at LCV-ER MCSs promotes Vap-, OSBP- and Sac1-dependent pathogen vacuole remodeling.

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“…For example, low levels of cellular cholesterol can result in endosomes forming MCS with the ER rather than continuing to be trafficked along microtubules (Rocha et al 2009 ). Important for this review, there is increasing evidence that MCS play crucial roles in host pathogen interactions, with both viral (Amako et al 2009 , Roulin et al 2014 , McCune et al 2017 , Ishikawa-Sasaki et al 2018 ) and bacterial pathogens (Auweter et al 2012 , Elwell and Engel 2012 , Derré 2017 , Justis et al 2017 , Stanhope and Derré 2018 , Ende et al 2022 , Vormittag et al 2023 ) using MCS to establish and maintain infection.…”

Section: Membrane Contact Sites In Health and Diseasementioning

confidence: 99%

Pathogen vacuole membrane contact sites – close encounters of the fifth kind

et al. 2023

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Vesicular trafficking and membrane fusion are well-characterized, versatile, and sophisticated means of ‘long range’ intracellular protein and lipid delivery. Membrane contact sites (MCS) have been studied in far less detail, but are crucial for ‘short range’ (10-30 nm) communication between organelles, as well as between pathogen vacuoles and organelles. MCS are specialized in the non-vesicular trafficking of small molecules such as calcium and lipids. Pivotal MCS components important for lipid transfer are the VAP receptor/tether protein, oxysterol binding proteins (OSBPs), the ceramide transport protein CERT, the phosphoinositide phosphatase Sac1, and the lipid phosphatidylinositol 4-phosphate (PtdIns(4)P). In this review, we discuss how these MCS components are subverted by bacterial pathogens and their secreted effector proteins to promote intracellular survival and replication.

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Making Contact: VAP Targeting by Intracellular Pathogens

Cited by 8 publications

References 12 publications

Global Proximity Interactome of the Human Macroautophagy Pathway

Global Proximity Interactome of the Human Macroautophagy Pathway

TheLegionella-driven PtdIns(4)Pgradient at LCV-ER membrane contact sites promotes Vap-, OSBP- and Sac1-dependent pathogen vacuole remodeling

Pathogen vacuole membrane contact sites – close encounters of the fifth kind

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