Cholesterol-binding molecules MLN64 and ORP1L mark distinct late endosomes with transporters ABCA3 and NPC1

Kant, Rik van der; Zondervan, Ilse; Janssen, Lennert; Neefjes, Jacques

doi:10.1194/jlr.m037325

Cited by 90 publications

(72 citation statements)

References 41 publications

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“…The bridge containing ORP1L also contains VAP (Rocha et al, 2009), but the fact that ORP1L is not anchored into endosome membranes suggests that it mediates a more labile tethering between the ER and LE. Recently, it was proposed that STARD3 and ORP1L are present in two LE subpopulations (van der Kant et al, 2013), which is consistent with our experiments showing that silencing of ORP1L did not modify STARD3-induced ER-LE contacts. Of interest, another START protein, CERT (ceramide transfer protein or STARD11), was proposed to function at contact sites.…”

Section: Discussionsupporting

confidence: 82%

See 1 more Smart Citation

STARD3/STARD3NL and VAP make a novel molecular tether between late endosomes and the ER

Alpy

Rousseau

Schwab

et al. 2013

Journal of Cell Science

213

254

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SummaryInter-organelle membrane contacts sites (MCSs) are specific subcellular regions favoring the exchange of metabolites and information. We investigated the potential role of the late-endosomal membrane-anchored proteins StAR related lipid transfer domain-3 (STARD3) and STARD3 N-terminal like (STARD3NL) in the formation of MCSs involving late-endosomes (LEs). We demonstrate that both STARD3 and STARD3NL create MCSs between LEs and the endoplasmic reticulum (ER). STARD3 and STARD3NL use a conserved two phenylalanines in an acidic tract (FFAT)-motif to interact with ER-anchored VAP proteins. Together, they form an LE-ER tethering complex allowing heterologous membrane apposition. This LE-ER tethering complex affects organelle dynamics by altering the formation of endosomal tubules. An in situ proximity ligation assay between STARD3, STARD3NL and VAP proteins identified endogenous LE-ER MCS. Thus, we report here the identification of proteins involved in inter-organellar interaction.

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Section: Discussionsupporting

confidence: 82%

“…STARD3 was recently proposed to be involved in cholesterol transport between LE and the plasma membrane (van der Kant et al, 2013). Although we cannot rule out this possibility, our data support a model in which STARD3 is primarily involved in cholesterol exchange and/or sensing between LEs and the ER.…”

Section: Discussionsupporting

confidence: 64%

STARD3/STARD3NL and VAP make a novel molecular tether between late endosomes and the ER

Alpy

Rousseau

Schwab

et al. 2013

Journal of Cell Science

213

254

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“…Such a misrouting effect could be caused by a decreased flux of cholesterol from late endosomes to lysosomes with an upregulation of alternative trafficking pathways from late endosomes to the ER. In support of this notion, there is increasing evidence of contact sites between late endosomes and the ER [46][47][48] , as well as evidence for direct vesicular and non-vesicular transport of cholesterol to the ER from late endosomes 49,50 .…”

Section: Discussionmentioning

confidence: 75%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.

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“…Alternatively, stable ORP1L-VAP membrane contacts could facilitate cholesterol transfer by another sterol binding protein located at the endosome-ER interface such as STARD3/MLN64. STARD3/MLN64 and ORP1L are thought to regulate sterol handling in two stages, with cholesterol first entering STARD3/MLN64 "early" late endosomes, from which it can be recycled to the plasma membrane before reaching the ORP1L/NPC1-positive "late" late endosomes that mediate cholesterol export to ER (79). However, a minor fraction of STARD3/MLN64 and ORP1L colocalizes in the same vesicles, suggesting that both molecules could be present in RID␣-induced endosome maturation intermediates (79).…”

Section: Discussionmentioning

confidence: 99%

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Cianciola

Chung

Manor

et al. 2017

J Virol

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Human adenoviruses (Ads) generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, we wished to determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RID␣ via its direct interaction with the sterol-binding protein ORP1L, a member of the evolutionarily conserved family of oxysterol-binding protein (OSBP)-related proteins (ORPs). Second, we wished to determine how this interaction regulates innate immunity to adenovirus. ORP1L is known to form highly dynamic contacts with endoplasmic reticulum-resident VAP proteins that regulate late endosome function under regulation of Rab7-GTP. Our studies have demonstrated that ORP1L-VAP complexes also support transport of LDL-derived cholesterol from endosomes to the endoplasmic reticulum, where it was converted to cholesteryl esters stored in lipid droplets when ORP1L was bound to RID␣. The virally induced mechanism counteracted defects in the predominant cholesterol transport pathway regulated by the late endosomal membrane protein Niemann-Pick disease type C protein 1 (NPC1) arising during early stages of viral infection. However, unlike NPC1, RID␣ did not reconstitute transport to endoplasmic reticulum pools that regulate SREBP transcription factors. RID␣-induced lipid trafficking also attenuated proinflammatory signaling by Toll-like receptor 4, which has a central role in Ad pathogenesis and is known to be tightly regulated by cholesterol-rich "lipid rafts." Collectively, these data show that RID␣ utilizes ORP1L in a way that is distinct from its normal function in uninfected cells to fine-tune lipid raft cholesterol that regulates innate immunity to adenovirus in endosomes.IMPORTANCE Early region 3 proteins encoded by human adenoviruses that attenuate immune-mediated pathology have been a particularly rich source of information regarding intracellular protein trafficking. Our studies with the early region 3-encoded RID␣ protein also provided fundamental new information regarding mechanisms of nonvesicular lipid transport and the flow of molecular information at membrane contacts between different organelles. We describe a new pathway that delivers cholesterol from endosomes to the endoplasmic reticulum, where it is esterified and stored in lipid droplets. Although lipid droplets are attracting renewed interest from the standpoint of normal physiology and human diseases, including those resulting from viral infections, experimental model systems for evaluating how and why they accumulate are still limited. Our studies also revealed an intriguing relationship between lipid droplets and innate immunity that may represent a new paradigm for viruses utilizing these organelles.KEYWORDS adenoviruses, cholesterol, endocytic pathway, endoplasmic reticulum, lipid droplet

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Cholesterol-binding molecules MLN64 and ORP1L mark distinct late endosomes with transporters ABCA3 and NPC1

Cited by 90 publications

References 41 publications

STARD3/STARD3NL and VAP make a novel molecular tether between late endosomes and the ER

STARD3/STARD3NL and VAP make a novel molecular tether between late endosomes and the ER

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

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