Endoplasmic Reticulum Membrane Contact Sites, Lipid Transport, and Neurodegeneration

Guillén-Samander, Andrés; Camilli, Pietro De

doi:10.1101/cshperspect.a041257

Cited by 21 publications

(24 citation statements)

References 185 publications

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“…We next asked how VPS13B was associated with the cis-/medial Golgi. VPS13B contains a lipid transfer domain along its entire length, with a VPS13 adaptor binding domain (VAB), an ATG2-C domain and a PH-like domain at the C-terminus (CT) 29, 30 . We hypothesized that the PH-like domain of VPS13B might be responsible for targeting VPS13B to the Golgi by binding to phosphatidylinositol 4-phosphate (PI4P) on Golgi membranes.…”

Section: Resultsmentioning

confidence: 99%

Sec23IP recruits the Cohen syndrome factor VPS13B/COH1 to ER exit site-Golgi interface for tubular ERGIC formation

Du,

Fan,

Song

et al. 2024

Preprint

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VPS13B/COH1 is the only known causative factor for Cohen syndrome, an early-onset autosomal recessive developmental disorder with intellectual inability, developmental delay, joint hypermobility, myopia and facial dysmorphism as common features, but the molecular basis of VPS13B/COH1 in pathogenesis is unknown. Here, we identify Sec23 interacting protein (Sec23IP) at ER exit site (ERES) as a VPS13B adaptor that recruits VPS13B to ERES-Golgi interfaces. VPS13B interacts directly with Sec23IP via the VPS13 adaptor binding domain (VAB), and the interaction promotes the association between ERES and the Golgi. Disease-associated missense mutations of VPS13B-VAB impair the interaction with Sec23IP. Knockout of VPS13B or Sec23IP blocks the formation of tubular ERGIC, an unconventional cargo carrier that expedites ER-to-Golgi transport. In addition, depletion of VPS13B or Sec23IP delays ER export of procollagen, suggesting a link between procollagen secretion and joint laxity in patients with Cohen disease. Together, our study reveals a crucial role of VPS13B-Sec23IP interaction at ERES-Golgi interface in the pathogenesis of Cohen syndrome.

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Section: Resultsmentioning

confidence: 99%

Sec23IP recruits the Cohen syndrome factor VPS13B/COH1 to ER exit site-Golgi interface for tubular ERGIC formation

Du,

Fan,

Song

et al. 2024

Preprint

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“…VAP is an endoplasmic reticulum (ER)-associated protein that tethers ER with other organelles such as endosomes and mitochondria, and its dysfunction is implicated in Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and frontotemporal dementia (Dong et al, 2016; Gomez-Suaga et al, 2019; Guillen-Samander and De Camilli, 2022; Lindhout et al, 2019; Teuling et al, 2007). VAP is present in two isoforms, VAPA and VAPB (Guillen-Samander and De Camilli, 2022). As one isoform can compensate for the absence of the other, we deleted both isoforms for our gene deletion experiments.…”

Section: Resultsmentioning

confidence: 99%

“…VAP is an ER resident protein found in membrane contact sites with various organelles such as Golgi, mitochondria, peroxisomes, endolysosomes, and plasma membrane. It plays an essential role in lipid transfer between these organelles (Guillen-Samander and De Camilli, 2022). VAP is present in two isoforms, VAPA and VAPB.…”

Section: Discussionmentioning

confidence: 99%

“…Using advances in proximity-labeled mitochondrial proteome labeling and imaging mitochondrial-actin tethering and stabilization (Hung et al, 2017; Lam et al, 2015; Schiavon et al, 2020), we have identified novel proteins tethering mitochondria to actin exclusively in dendrites. In addition, we find that the vesicle-associated membrane protein-associated protein (VAP) (Gomez-Suaga et al, 2019; Guillen-Samander and De Camilli, 2022; Teuling et al, 2007) plays a central role in stabilizing dendritic mitochondria for long durations of synaptic plasticity formation and maintenance, and determining the spatial segment supported during synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

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VAP spatially stabilizes dendritic mitochondria to locally fuel synaptic plasticity

Bapat

Purimetla

Kruessel

et al. 2023

Preprint

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Synapses are pivotal sites of memory formation and undergo plasticity in response to external inputs. Consequently, synapses are hotspots of energy consumption and are susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via cytoskeletal tethering and serve as local energy supplies to fuel synaptic plasticity. However, the mechanisms that tether and stabilize neuronal mitochondria for long durations and determine the spatial dendritic segment supported during synaptic plasticity are unknown. We identified a list of novel mitochondrial-cytoskeletal interactors in neurons using APEX-based proximity labeling. We narrowed down the protein candidates that exclusively tether mitochondria to actin near postsynaptic spines using high-resolution Airyscan confocal imaging. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in Amyotrophic Lateral Sclerosis and interacts with the endoplasmic reticulum, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we investigated individual spines stimulated by two-photon glutamate uncaging for spine plasticity induction and their adjacent spines. We find that, along with actin, VAP functions as a spatial stabilizer of mitochondrial compartments to sustain synaptic plasticity for up to ~60 min and as a spatial ruler that determines the ~30 μm length of the dendritic segment supporting synaptic plasticity.

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“…This mode of lipid transport is critically important as most lipid species in eukaryotic cells are synthesized within the ER. Thus, homeostasis of PM lipids, which is needed to support the structural and signaling functions of this membrane, requires rapid and efficient exchanges of lipids between the ER and the PM both for the delivery of newly synthesized lipids and for the return to the ER of lipid catabolites for metabolic recycling (Guillén-Samander and De Camilli, 2023).…”

Section: Introductionmentioning

confidence: 99%

A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts

Johnson,

Iuliano,

Lam

et al. 2023

Preprint

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Junctions between the ER and the plasma membrane (ER/PM junctions) are implicated in calcium homeostasis, non-vesicular lipid transfer and other cellular functions. Two ER proteins that function both as membrane tethers to the PM via a polybasic motif in their C-terminus and as phospholipid transporters are brain-enriched TMEM24 (C2CD2L) and its paralog C2CD2. Based on an unbiased proximity ligation analysis, we found that both proteins can also form a complex with band 4.1 family members, which in turn can bind a variety of plasma membrane proteins including cell adhesion molecules such as SynCAM 1. This complex results in the enrichment of TMEM24 and C2CD2 containing ER/PM junctions at sites of cell contacts. Dynamic properties of TMEM24-dependent ER/PM contacts are impacted when in complex as TMEM24 present at cell adjacent junctions is not shed by calcium rise, unlike TMEM24 at non-cell adjacent junctions. These findings suggest that cell-contact interactions control ER/PM junctions via TMEM24 complexes involving band 4.1 proteins.SUMMARYThe ER-anchored lipid transfer proteins TMEM24/C2CD2L and its paralog C2CD2 mediate formation of ER-plasma membrane junctions at sites of cell-cell contacts by interacting with band 4.1 family members and indirectly with cell adhesion proteins.

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Endoplasmic Reticulum Membrane Contact Sites, Lipid Transport, and Neurodegeneration

Cited by 21 publications

References 185 publications

Sec23IP recruits the Cohen syndrome factor VPS13B/COH1 to ER exit site-Golgi interface for tubular ERGIC formation

Sec23IP recruits the Cohen syndrome factor VPS13B/COH1 to ER exit site-Golgi interface for tubular ERGIC formation

VAP spatially stabilizes dendritic mitochondria to locally fuel synaptic plasticity

A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts

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