Box C/D Small Nucleolar RNA (snoRNA) U60 Regulates Intracellular Cholesterol Trafficking

Brandis, Katrina; Gale, Sarah E.; Jinn, Sarah; Langmade, S. Joshua; Dudley-Rucker, Nicole; Jiang, Hui; Sidhu, Rohini; Ren, Aileen; Goldberg, Anna Carla; Schaffer, Jean E.; Ory, Daniel S.

doi:10.1074/jbc.m113.488577

Cited by 45 publications

(45 citation statements)

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“…Importantly, assays that solely rely on detecting the association with fibrillarin (71) will miss these previously unidentified, noncanonical functions, because they do not take localization in a fibrillarin-free fraction into account. It is possible that the unexpected role of SNORD60 in intracellular cholesterol trafficking is caused through a fibrillarin-free RNP acting on pre-mRNAs and not through rRNA methylation (19).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the loss of SNORD116 expression is a decisive factor in Prader-Willi syndrome, the most common genetic cause for hyperphagia and obesity (17,18). SNORD60 is involved in intracellular cholesterol trafficking, which is independent of its suggested function in rRNA methylation (19), and SNORDs U32a, U33, and U35a mediate lipotoxic stress, possibly through their cytosolic function (20). Although SNORDs are considered housekeeping genes, the expression of some SNORDs is altered in cancer.…”

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confidence: 99%

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Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

Falaleeva

Pagès

Matuszek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

158

152

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C/D box small nucleolar RNAs (SNORDs) are small noncoding RNAs, and their best-understood function is to target the methyltransferase fibrillarin to rRNA (for example, SNORD27 performs 2′-Omethylation of A27 in 18S rRNA). Unexpectedly, we found a subset of SNORDs, including SNORD27, in soluble nuclear extract made under native conditions, where fibrillarin was not detected, indicating that a fraction of the SNORD27 RNA likely forms a protein complex different from canonical snoRNAs found in the insoluble nuclear fraction. As part of this previously unidentified complex, SNORD27 regulates the alternative splicing of the transcription factor E2F7 pre-mRNA through direct RNA-RNA interaction without methylating the RNA, likely by competing with U1 small nuclear ribonucleoprotein (snRNP). Furthermore, knockdown of SNORD27 activates previously "silent" exons in several other genes through base complementarity across the entire SNORD27 sequence, not just the antisense boxes. Thus, some SNORDs likely function in both rRNA and pre-mRNA processing, which increases the repertoire of splicing regulators and links both processes.alternative splicing | gene regulation | snoRNAs | pre-mRNA processing S mall nucleolar RNAs (snoRNAs) are 60-to 300-nt-long noncoding RNAs that accumulate in the nucleolus. Based on conserved sequence elements, snoRNAs are classified as C/D box small nucleolar RNAs (SNORDs) or H/ACA box snoRNAs (SNORAs). SNORDs contain sequence elements termed C (RUGAUGA) and D (CUGA) boxes, usually present in duplicates (C′ and D′ boxes), and up to two antisense boxes that hybridize to the target RNA (1). In humans, SNORDs are usually derived from introns. After the splicing reaction, introns are excised as lariats, which are then opened by the debranching enzyme and subsequently degraded. Intronic SNORDs escape this degradation by forming a protein complex that consists of non-histone chromosome protein 2-like 1 (NHP2L1, 15.5K, SNU13), nucleolar protein 5A (NOP56), nucleolar protein 5 (NOP58), and fibrillarin (2-4). The SNORD protein complex forms through the entry of the snoRNA and fibrillarin to a complex containing NHP2L1, NOP58, and at least five assembly factors (5). The SNORD acts as a scaffold for the final protein complex formation and also controls recognition of other RNAs using the antisense boxes. The antisense boxes recognize sequences in rRNA, resulting in the fifth nucleotide upstream of the D or D′ box being 2′-O-methylated by fibrillarin (1). Structural studies indicate that the active form of SNORDs is dimeric (6).The conserved overall structure of SNORDs allows the identification of their putative target RNA binding sites. However, numerous SNORDs without obvious target RNAs have been identified (7-10) and are termed "orphan snoRNAs." Genome-wide deep sequencing experiments identified shorter but stable SNORD fragments that were found in all species tested, ranging from mammals to the protozoan Giardia lamblia (11) and EpsteinBarr virus (12). Fragments longer than 27 nt generated by SNORDs will ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

Falaleeva

Pagès

Matuszek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

158

152

View full text Add to dashboard Cite

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“…The majority of cellular cholesterol is located at the PM. Partial defects in PM-to-ER cholesterol transport are known to increase cholesterol synthesis (31). To directly explore whether aberrant activation of the SREBP-2 pathway in Abca1 Ϫ/Ϫ cells is due to impaired sterol delivery to the ER, we assessed PM-to-ER sterol movement by using multiple intracellular sterol trafficking assays.…”

Section: Abca1 Deficiency Leads To Hyperactivation Of Srebp-2mentioning

confidence: 99%

Deficiency in the Lipid Exporter ABCA1 Impairs Retrograde Sterol Movement and Disrupts Sterol Sensing at the Endoplasmic Reticulum

Yamauchi

Iwamoto

Rogers

et al. 2015

Journal of Biological Chemistry

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Background:Little is known about how mammalian cells modulate retrograde sterol transport for cellular cholesterol homeostasis. Results: ABCA1 deficiency impairs endocytic retrograde sterol transport to the endoplasmic reticulum and activates the SREBP-2 pathway. Conclusion: ABCA1 participates in bidirectional sterol movement at the plasma membrane to regulate cellular cholesterol homeostasis. Significance: A novel function of ABCA1 is identified.

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“…3 ). Finally, we assessed the ability of 25-HCTL to bind to LXR, a nuclear hormone receptor that is activated by side-chain oxysterols and promotes cholesterol ethanol vehicle in normal media containing [d7]linoleate-BSA ( 28 ). Cells were harvested from 0 to 18 h, lipids extracted, and incorporation of oxysterols into oxysterol linoleate esters quantifi ed by LC-MS/MS.…”

Section: Comparison Of the Effects Of 25-hc And 25-hctl On Regulationmentioning

confidence: 99%

“…Cholesterol esterifi cation was performed as previously described ( 28 ). Briefl y, cells were pulsed with 1 Ci/ml [ …”

Section: Basal Cholesterol Esterifi Cation Assaymentioning

confidence: 99%

A novel intrinsically fluorescent probe for study of uptake and trafficking of 25-hydroxycholesterol

Iaea

Gale

Bielska

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org by coordinated homeostatic mechanisms, primarily involving the regulated proteolysis of the sterol regulatory element-binding protein (SREBP)-2 transcription factor in the Golgi ( 1 ). When ER sterols are abundant, SREBP-2 is retained in the ER in a complex with the cholesterol-sensing protein, SREBP cleavage-activating protein (SCAP), and the ER retention proteins, Insig-1 or -2 ( 2, 3 ). When cholesterol content in the ER is depleted, SCAP undergoes a conformational change and is released from Insig, allowing the SREBP-SCAP complex to translocate to the Golgi apparatus ( 4, 5 ) where it undergoes proteolytic maturation with release of the SREBP transcription factor ( 6 ).Cholesterol homeostasis is regulated not only by cholesterol, but also by oxygenated cholesterol species, referred to as oxysterols ( 1, 7-9 ) Side-chain oxysterols, such as 25-hydroxycholesterol (25-HC), are generated enzymatically and act as important regulators of cholesterol homeostasis, despite their presence in cells being only at 0.1% the concentration of cholesterol ( 9 ). At the transcriptional level, 25-HC can bind the liver X receptors (LXRs) to active LXR-mediated transcription that results in increased cholesterol effl ux and elimination ( 10, 11 ). 25-HC also inhibits SREBP maturation and subsequent transcription of genes involved in cholesterol biosynthesis and uptake ( 1 ). In contrast to cholesterol, which directly interacts with SCAP, 25-HC enhances the interaction between SCAP and Insig proteins, resulting in retention of the SREBP-2-SCAP complex in the ER ( 12, 13 ).

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Box C/D Small Nucleolar RNA (snoRNA) U60 Regulates Intracellular Cholesterol Trafficking

Cited by 45 publications

References 43 publications

Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

Deficiency in the Lipid Exporter ABCA1 Impairs Retrograde Sterol Movement and Disrupts Sterol Sensing at the Endoplasmic Reticulum

A novel intrinsically fluorescent probe for study of uptake and trafficking of 25-hydroxycholesterol

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