Transmembrane Protein 55B Is a Novel Regulator of Cellular Cholesterol Metabolism

Medina, Marisa W.; Bauzon, Frederick; Naidoo, Devesh; Theusch, Elizabeth; Stevens, Kristen N.; Schilde, Jessica; Schubert, Christian; Mangravite, Lara M.; Rudel, Lawrence L.; Temel, Ryan E.; Runz, Heiko; Krauss, Ronald M.

doi:10.1161/atvbaha.113.302806

Cited by 19 publications

(11 citation statements)

References 26 publications

(30 reference statements)

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“…9e ). In agreement with the report by Medina et al 48 , we observed that the upregulation of TMEM55B induced by U18666A was significantly decreased in cells depleted of SREBF2 (Fig. 7f ); however, the decrease was even more pronounced in cells depleted of SREBF2, TFEB, and TFE3 (Fig.…”

Section: Resultssupporting

confidence: 93%

“…A previous study suggested that the levels of TMEM55B are modulated by the transcription factor SREBF2 in response to cholesterol levels 48 . In agreement with this report, we found that in HeLa cells, sterol depletion by treatment with a combination of lipo-protein depleted serum and statins caused a significant TMEM55B upregulation both to the mRNA and protein levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

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TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes

et al. 2017

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Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion. Alterations in lysosomal positioning contribute to different human pathologies, such as cancer, neurodegeneration, and lysosomal storage diseases. Here we report the identification of a novel mechanism of lysosomal trafficking regulation. We found that the lysosomal transmembrane protein TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubules minus-end. TMEM55B overexpression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery. TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress. TMEM55B or JIP4 depletion abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome–lysosome fusion. Overall our data suggest that the TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes

et al. 2017

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“…We confirmed that PIP5Kα knockdown significantly decreased whole cell PIP2 levels by 30% in RAW264.7 cells (Figure 5 I). Conversely, we knocked down Tmem55b, a specific PIP2 phosphatase that converts PIP2 to PI5P and has a role in cellular cholesterol metabolism 41 , whose expression we detected in RAW264.7 cells (Online Figure VIII A). This knockdown modestly, but significantly, increased cellular apoA1 binding, cholesterol efflux to apoA1, and whole cell PIP2 levels (Online Figure VIII B-D).…”

Section: Resultsmentioning

confidence: 99%

PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly

Gulshan

Brubaker

Conger

et al. 2016

Circulation Research

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Rationale The molecular mechanism by which ABCA1 mediates cellular binding of apolipoprotein A-I (apoA1) and nascent HDL assembly is not well understood. Objective To determine the cell surface lipid that mediates apoA1 binding to ABCA1 expressing cells and the role it plays in nascent HDL assembly. Methods and Results Using multiple biochemical and biophysical methods, we found that apoA1 binds specifically to phosphatidylinositol (4,5) bis-phosphate (PIP2). Flow cytometry and PIP2 reporter binding assays demonstrated that ABCA1 led to PIP2 redistribution from the inner to the outer leaflet of the plasma membrane. Enzymatic cleavage of cell surface PIP2 or decreased cellular PIP2 by knockdown of phosphatidylinositol-5-phosphate 4-kinase impaired apoA1 binding and cholesterol efflux to apoA1. PIP2 also increased the spontaneous solubilization of phospholipid liposomes by apoA1. Using site directed mutagenesis; we found that ABCA1's PIP2 and phosphatidylserine translocase activities are independent from each other. Furthermore, we discovered that PIP2 is effluxed from cells to apoA1, where it is associated with HDL in plasma, and that PIP2 on HDL is taken up by target cells in a scavenger receptor-BI (SR-BI) dependent manner. Mouse plasma PIP2 levels are apoA1 gene dosage dependent and are > 1 μM in apoA1 transgenic mice. Conclusions ABCA1 has a PIP2 floppase activity, which increases cell surface PIP2 levels that mediate apoA1 binding and lipid efflux during nascent HDL assembly. We found that PIP2 itself is effluxed to apoA1 and it circulates on plasma HDL, where it can be taken up via the HDL receptor SR-BI.

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“…Experiments were performed four times. Effects of RP1-13D10.2 overexpression on media levels of APOB were quantified by ELISA as previously described 21 . To measure the effect of RP1-13D10.2 overexpression on LDLR transcript stability, Huh7 cells were transfected for 48 hours with either the pCMV6-entry plasmid or the RP1-13D10.2 overexpression plasmids, treated with 1 μg/mL actinomycin D and harvested over 6 hours.…”

Section: Methodsmentioning

confidence: 99%

RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol

Mitchel¹,

Theusch²,

Cubitt³

et al. 2016

Circ Cardiovasc Genet

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Background Numerous genetic contributors to cardiovascular disease risk have been identified through genome-wide association studies (GWAS); however, identifying the molecular mechanism underlying these associations is not straightforward. The JUPITER trial of rosuvastatin users identified a sub-genome wide association of rs6924995, a SNP ~10kb downstream of MYLIP (aka IDOL, inducible degrader of LDLR), with LDL cholesterol statin response. Interestingly, though this signal was initially attributed to MYLIP, rs6924995 lies within RP1-13D10.2, an uncharacterized long noncoding RNA. Methods and Results Using simvastatin and sham incubated lymphoblastoid cell lines from participants of the Cholesterol and Pharmacogenetics simvastatin clinical trial, we found that statin induced change in RP1-13D10.2 levels differed between cell lines from the tails of the Caucasian and African American LDLC response distributions, while no difference in MYLIP was observed. RP1-13D10.2 overexpression in Huh7 and HepG2 increased LDLR transcript levels, increased LDL uptake, and decreased media levels of APOB. In addition, we found a trend of slight differences in the effects of RP1-13D10.2 overexpression on LDLR transcript levels between hepatoma cells transfected with the rs6924995 “A” vs. “G” allele, and a suggestion of an association between rs6924995 and RP1-10D13.2 expression levels in the CAP LCLs. Lastly, RP1-13D10.2 expression levels appear to be sterol regulated, consistent with its potential role as a novel lipid regulator. Conclusions RP1-13D10.2 is a long noncoding RNA that regulates LDLR and may contribute to LDLC response to statin treatment. These findings highlight the potential role of non-coding RNAs as determinants of inter-individual variation in drug response.

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Transmembrane Protein 55B Is a Novel Regulator of Cellular Cholesterol Metabolism

Cited by 19 publications

References 26 publications

TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes

TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes

PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly

RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol

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