Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1

Cianciola, Nicholas L.; Greene, Diane J.; Morton, Richard E.; Carlin, Cathleen R.

doi:10.1091/mbc.e12-10-0760

Cited by 39 publications

(53 citation statements)

References 77 publications

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“…These probably include proteins, such as the abovementioned VAP-A interactor MENTHO (Alpy et al, 2013) and the ORP5-interacting factor Hrs (Du et al, 2012). Other proteins, such as the adenovirus RIDa (receptor internalization and degradation) (Cianciola et al, 2013), the antiviral proteins interferon-induced transmembrane protein 3 (IFITM3) (Amini-Bavil-Olyaee et al, 2013) and oligoadenylate synthetase 1b (Oas1b) (Courtney et al, 2012) (Fig. 2) moderate cholesterol transfer and endosomal function at the ER-endosome interface, but exactly how is not known.…”

Section: Protein Pairs At the Er-endosome Interfacementioning

confidence: 99%

“…2) moderate cholesterol transfer and endosomal function at the ER-endosome interface, but exactly how is not known. Interestingly, expression of RIDa rescues the export of late endosomal cholesterol to the ER in NPC1-deficient cells (Cianciola et al, 2013). Finally, it is unclear how ORP1L-containing late endosomes are separated from those that contain MLN64.…”

Section: Protein Pairs At the Er-endosome Interfacementioning

confidence: 99%

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Small regulators, major consequences – Ca2+ and cholesterol at the endosome–ER interface

Kant

Neefjes

2014

Journal of Cell Science

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The ER is the largest cellular compartment and a major storage site for lipids and ions. In recent years, much attention has focused on contacts between the ER and other organelles, and one particularly intimate relationship is that between the ER and the endosomal system. ER-endosome contacts intensify when endosomes mature, and the ER participates in endosomal processes, such as the termination of surface receptor signaling, multi-vesicular body formation, and transport and fusion events. Cholesterol and Ca 2+ are transferred between the ER and endosomes, possibly acting as messengers for ER-endosome crosstalk. Here, we summarize different types of ER-endosomal communication and discuss membrane contact sites that might facilitate this crosstalk. We review the protein pairs that interact at the ER-endosome interface and find that many of these have a role in cholesterol exchange. We also summarize Ca 2+ exchange between the ER and endosomes, and hypothesize that ERendosome contacts integrate several cellular functions to guide endosomal maturation. We post the hypothesis that failure in ERendosome contacts is an unrecognized but important contributor to diseases, such as Niemann-Pick type C disease, Alzheimer's disease and amyotrophic lateral sclerosis.

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Section: Protein Pairs At the Er-endosome Interfacementioning

confidence: 99%

Section: Protein Pairs At the Er-endosome Interfacementioning

confidence: 99%

Small regulators, major consequences – Ca2+ and cholesterol at the endosome–ER interface

Kant

Neefjes

2014

Journal of Cell Science

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“…Our studies were the first to link an Ad-E3 protein to lipid trafficking (14)(15)(16). The E3 membrane protein RID␣ regulates the transport of LDL-cholesterol from endosomes to the endoplasmic reticulum (ER), where it is converted to cholesteryl esters (CEs) by acyl-coenzyme A:cholesterol acyltransferase (ACAT) and stored in lipid droplets (LDs) that bud off the ER (16)(17)(18).…”

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confidence: 99%

“…The E3 membrane protein RID␣ regulates the transport of LDL-cholesterol from endosomes to the endoplasmic reticulum (ER), where it is converted to cholesteryl esters (CEs) by acyl-coenzyme A:cholesterol acyltransferase (ACAT) and stored in lipid droplets (LDs) that bud off the ER (16)(17)(18). This lipid transport pathway is typically regulated in the host by two proteins, called NPC1 (localized to limiting membranes) and NPC2 (present in the lumen), of late endosomes and lysosomes (19,20).…”

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confidence: 99%

“…The original insight into the lipid trafficking properties of RID␣ arose from studies performed with NPC1-deficient cell models, including patient fibroblasts, where expression of the viral protein was sufficient to alleviate LSO formation by diverting excess free cholesterol to LDs (14,16). Acute gene silencing studies then led to identification of ORP1L as an essential host factor supporting RID␣-induced lipid trafficking in NPC1-deficient cells.…”

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confidence: 99%

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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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Bridging the molecular and biological functions of the oxysterol-binding protein family

Pietrangelo

Ridgway

2018

Cell. Mol. Life Sci.

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Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a large eukaryotic gene family that transports and regulates the metabolism of sterols and phospholipids. The original classification of the family based on oxysterol-binding activity belies the complex dual lipid-binding specificity of the conserved OSBP homology domain (OHD). Additional protein- and membrane-interacting modules mediate the targeting of select OSBP/ORPs to membrane contact sites between organelles, thus positioning the OHD between opposing membranes for lipid transfer and metabolic regulation. This unique subcellular location, coupled with diverse ligand preferences and tissue distribution, has identified OSBP/ORPs as key arbiters of membrane composition and function. Here, we will review how molecular models of OSBP/ORP-mediated intracellular lipid transport and regulation at membrane contact sites relate to their emerging roles in cellular and organismal functions.

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Adenovirus RIDα uncovers a novel pathway requiring ORP1L for lipid droplet formation independent of NPC1

Cited by 39 publications

References 77 publications

Small regulators, major consequences – Ca2+ and cholesterol at the endosome–ER interface

Small regulators, major consequences – Ca2+ and cholesterol at the endosome–ER interface

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

Bridging the molecular and biological functions of the oxysterol-binding protein family

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