Fat-specific protein 27 modulates nuclear factor of activated T cells 5 and the cellular response to stress

Ueno, Masaki; Shen, Wen-Jun; Patel, Shushma; Greenberg, Andrew S.; Azhar, Salman; Kraemer, Fredric B.

doi:10.1194/jlr.m033365

Cited by 50 publications

(46 citation statements)

References 43 publications

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“…It is possible that under hypertonicity another factor compensates for TonEBP absence to maintain IL6 and TNF␣ protein levels at the post-transcriptional stage. Previous reports have demonstrated hypertonic induction of CCL2, IL6, and TNF (12,24), which was TonEBPdependent in some instances. On the other hand, hypertonicity suppressed LPS-mediated IL6 production in macrophages (16).…”

Section: Discussionmentioning

confidence: 99%

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells

Johnson

Shapiro

Risbud

2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerTranscription factor tonicity-responsive enhancer-binding protein (TonEBP/NFAT5) is critical for osmo-adaptation and extracellular matrix homeostasis of nucleus pulposus (NP) cells in their hypertonic tissue niche. Recent studies implicate TonEBP signaling in inflammatory disease and rheumatoid arthritis pathogenesis. However, broader functions of TonEBP in the disc remain unknown. RNA sequencing was performed on NP cells with TonEBP knockdown under hypertonic conditions. 1140 TonEBP-dependent genes were identified and categorized using Ingenuity Pathway Analysis. Bioinformatic analysis showed enrichment of matrix homeostasis and cytokine/ chemokine signaling pathways. C-C motif chemokine ligand 2 (CCL2), interleukin 6 (IL6), tumor necrosis factor (TNF), and nitric oxide synthase 2 (NOS2) were studied further. Knockdown experiments showed that TonEBP was necessary to maintain expression levels of these genes. Gain-and loss-of-function experiments and site-directed mutagenesis demonstrated that TonEBP binding to a specific site in the CCL2 promoter is required for hypertonic inducibility. Despite inhibition by dominant-negative TonEBP, IL6 and NOS2 promoters were not hypertonicity-inducible. Whole-disc response to hypertonicity was studied in an ex vivo organ culture model, using wild-type and haploinsufficient TonEBP mice. Pro-inflammatory targets were induced by hypertonicity in discs from wild-type but not TonEBP-haploinsufficient mice. Mechanistically, NF-B activity increased with hypertonicity and was necessary for hypertonic induction of target genes IL6, TNF, and NOS2 but not CCL2. Although TonEBP maintains transcription of genes traditionally considered pro-inflammatory, it is important to note that some of these genes also serve anabolic and pro-survival roles. Therefore, in NP cells, this phenomenon may reflect a physiological adaptation to diurnal osmotic loading of the intervertebral disc.The intervertebral disc is well suited to fulfill its mechanical role in the human spine, where it permits flexion and rotation, and absorbs compressive loads (1). The matrix-rich nucleus pulposus (NP) 2 at the center of the disc gives the tissue its ability to resist compression through high osmotic swelling pressure (2-4), loss of which correlates with degeneration and back pain (5). Although the high fixed charge density of the aggrecan-rich matrix allows the nucleus pulposus its water-imbibing properties, it also results in a hypertonic environment for NP cells. Importantly, tonicity of the extracellular environment fluctuates widely with diurnal cycle: water is forced out of the disc during the day when the spine is loaded and imbibed during the unloaded phase at night (6).In mammalian cells, a key transcription factor TonEBP (NFAT5) is activated by elevated hypertonicity and promotes transcription of genes that produce or transport organic osmolytes (7). In addition, TonEBP controls transcription of several genes that are important for cell survival under hypertonic conditions independ...

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Section: Discussionmentioning

confidence: 99%

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells

Johnson

Shapiro

Risbud

2016

Journal of Biological Chemistry

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“…NFAT5 was also documented to be part of a bulky complex, which consists of several other partners, such as catalytic subunit of PKA [9], ATM [10], RNA Helicase A [11], TAZ [12], FSP27 [13], β-catenin [14], AP-1 [15], HSP-90 [16] and PARP1 [16]. Among these interacting partners, PARP1, an inhibitor of transcriptional activity of NFAT5 [16], catalyzes poly (ADP-ribosyl)ation of proteins, as well as plays a role in DNA repair mechanism using NAD + as cofactor [17].…”

Section: Introductionmentioning

confidence: 98%

SIRT1 contributes to aldose reductase expression through modulating NFAT5 under osmotic stress: In vitro and in silico insights

Timuçin

Bodur

Başağa

2015

Cellular Signalling

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“…Horien artean FSP27 proteina dago. FSP27-k NFAT5 (nuclear factor of activated T cells 5; aktibatutako T zelulen faktore nuklearra 5) transkripzio-faktorea bahitzen du, eta nukleora sartzea oztopatuz bere jarduera murrizten du [23]. NFAT5 transkripzio-faktoreak estres hipertonikoari eta estimulu ugariri aurre egiteko erregulatzen du gene-adierazpena [24,25] eta, beraz, LTek homeostasiaren modulazioan dihardutela esan daiteke.…”

Section: Zitosoleko Lipido-tanten Sorrera Eta Erabileraunclassified

Zitosoleko lipido-tanten sorrera eta erabilera

Navarro-Imaz

Arisqueta

Rueda

et al. 2017

EKAIA

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Laburpena: Lipido-tantak klasikoki lipido-biltegi inertetzat hartu badira ere, gaur egun benetako organulutzat hartzen dira, beren konplexutasunagatik eta metabolismoan eta zelulen beste fenomenoetan dituzten zereginengatik. Erretikulu endoplasmatikoan sortu eta bertatik askatu ondoren, beren bizitzan zehar hazi egiten dira, lipidoen eta proteinen transferentzia egiten dute, fusio prozesuetan hartzen dute parte eta elkarrekintza espezifikoak izaten dituzte beste organuluekin. Gordetzen dituzten lipidoak erregai zein beste molekula batzuen aitzindari gisa erabiltzen dira, eta horretarako lipolisi eta lipofagia prozesuen bidez askatzen dituzte modu erregulatuan. Lan honetan laburki aztertzen dira prozesu horiek eta lipido-tantek betetzen dituzten funtzio ezkanonikoak.Hitz gakoak: lipido-tantak, lipidoen metaketa, funtzio ezkanonikoak. Abstract:Although lipid droplets (LD) have traditionally been considered inert lipid deposits nowadays they are considered true organelles given their complexity and involvement in metabolism and other cellular processes. LDs originate in endoplasmic reticulum and after release they show growth, transference of lipids and proteins, fusion or specific interactions with other organelles. Lipids stored in LDs can be used as fuel or metabolic precursors, and for such purposes they are released in tightly controlled lipolysis or lipophagy processes. This work summarises all these aspects as well as other non-canonical LD functions.

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Fat-specific protein 27 modulates nuclear factor of activated T cells 5 and the cellular response to stress

Cited by 50 publications

References 43 publications

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells

SIRT1 contributes to aldose reductase expression through modulating NFAT5 under osmotic stress: In vitro and in silico insights

Zitosoleko lipido-tanten sorrera eta erabilera

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