Nuclear import of a lipid-modified transcription factor

Eisenhaber, Birgit; Sammer, Michaela; Lua, Wai Heng; Benetka, Wolfgang; Liew, Lai Ling; Yu, Weimiao; Lee, Hwee Kuan; Koranda, Manfred; Eisenhaber, Frank; Adhikari, Subash

doi:10.4161/cc.10.22.18043

Cited by 32 publications

(22 citation statements)

References 51 publications

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“…According to the aforementioned findings, the abundance of κ-actin was significantly increased in biomechanically stimulated VSMCs (Figures 3A,B ). As earlier results suggested that NFAT5 activity is regulated by stretch-dependent palmitoylation (Eisenhaber et al, 2011 ; Scherer et al, 2014 ) we assumed that the class of carnitine palmitoyl transferases is crucial for the palmitoylation process and thus NFAT5 activity and κ-actin expression. We scrutinized this hypothesis by investigating stretch-induced nuclear translocation of NFAT5 in VSMCs which were treated with etomoxir—an inhibitor of the mitochondrial carnitine palmitoyltransferase 1 that is tested in clinical trials for its capacity to treat congestive heart failure (Holubarsch et al, 2007 ).…”

Section: Resultsmentioning

confidence: 80%

“…However, its palmitoylation appears to be crucial for the stretch-induced nuclear translocation—a covalent attachment of fatty acids to cysteine, sometimes serine and threonine residues of the protein core. Such a modification has been reported to regulate the entry of NFAT5 into the nucleus in response to osmotic stress (Eisenhaber et al, 2011 ). Additionally, our study suggests that the activity of type 1 carnitine palmitoyl transferases (CPT1) is rate-limiting for the translocation process occurring in VSMCs upon exposure to biomechanical stretch.…”

Section: Discussionmentioning

confidence: 99%

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TonEBP/NFAT5 regulates ACTBL2 expression in biomechanically activated vascular smooth muscle cells

et al. 2014

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Cytoskeletal reorganization and migration are critical responses which enable vascular smooth muscle cells (VSMCs) cells to evade, compensate, or adapt to alterations in biomechanical stress. An increase in wall stress or biomechanical stretch as it is elicited by arterial hypertension promotes their reorganization in the vessel wall which may lead to arterial stiffening and contractile dysfunction. This adaptive remodeling process is dependent on and driven by subtle phenotype changes including those controlling the cytoskeletal architecture and motility of VSMCs. Recently, it has been reported that the transcription factor nuclear factor of activated T-cells 5 (TonEBP/NFAT5) controls critical aspects of the VSMC phenotype and is activated by biomechanical stretch. We therefore hypothesized that NFAT5 controls the expression of gene products orchestrating cytoskeletal reorganization in stretch-stimulated VSMCs. Automated immunofluorescence and Western blot analyses revealed that biomechanical stretch enhances the expression and nuclear translocation of NFAT5 in VSMCs. Subsequent in silico analyses suggested that this transcription factor binds to the promotor region of ACTBL2 encoding kappa-actin which was shown to be abundantly expressed in VSMCs upon exposure to biomechanical stretch. Furthermore, ACTBL2 expression was inhibited in these cells upon siRNA-mediated knockdown of NFAT5. Kappa-actin appeared to be aligned with stress fibers under static culture conditions, dispersed in lamellipodia and supported VSMC migration as its knockdown diminishes lateral migration of these cells. In summary, our findings delineated biomechanical stretch as a determinant of NFAT5 expression and nuclear translocation controlling the expression of the cytoskeletal protein ACTBL2. This response may orchestrate the migratory activity of VSMCs and thus promote maladaptive rearrangement of the arterial vessel wall during hypertension.

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Section: Resultsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

TonEBP/NFAT5 regulates ACTBL2 expression in biomechanically activated vascular smooth muscle cells

et al. 2014

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“…This study showed that the shortest isoform of NFAT5 (isoform a, which does not contain NES) is anchored to the plasma membrane via myristoylation and palmitoylation at the second (Gly2) and fifth (Cys5) residue of the protein respectively under a resting state, but that it undergoes nuclear import upon hypertonic induction [72]. How this NFAT5 isoform is detached from the plasma membrane upon hypertonic stress remains unknown, but it might represent an alternative mechanism to limit the nuclear import of this NES-deficient NFAT5 isoform to prevent aberrant gene transcription.…”

Section: Regulation Of Nuclear Abundancementioning

confidence: 99%

NFAT5 in cellular adaptation to hypertonic stress – regulations and functional significance

Cheung

2013

JMS

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The Nuclear Factor of Activated T Cells-5 (NFAT5), also known as OREBP or TonEBP, is a member of the nuclear factors of the activated T cells family of transcription factors. It is also the only known tonicity-regulated transcription factor in mammals. NFAT5 was initially known for its role in the hypertonic kidney inner medulla for orchestrating a genetic program to restore the cellular homeostasis. Emerging evidence, however, suggests that NFAT5 might play a more diverse functional role, including a pivotal role in blood pressure regulation and the development of autoimmune diseases. Despite the growing significance of NFAT5 in physiology and diseases, our understanding of how its activity is regulated remains very limited. Furthermore, how changes in tonicities are converted into functional outputs via NFAT5 remains elusive. Therefore, this review aims to summarize our current knowledge on the functional roles of NFAT5 in osmotic stress adaptation and the signaling pathways that regulate its activity.

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“…IV) Finally, it is important to note that SIRT6 may directly induce several post translational modifications including deacetylation and/or depalmitoylation on NFAT5 for upregulation of AR [ 12 ]. One intriguing example would be the case of depalmitoylation of NFAT5, which resulted in its nuclear translocation [ 44 ]. Since hydrolysis of long chain fatty acids by SIRT6 was suggested to increase its deacetylase activity and deacetylation has been suggested to activate NFAT5, SIRT6 may also be considered as direct factor regulating NFAT5 and AR [ 9 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

SIRT6 Is a Positive Regulator of Aldose Reductase Expression in U937 and HeLa cells under Osmotic Stress: In Vitro and In Silico Insights

Timuçin

Başağa

2016

PLoS ONE

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SIRT6 is a protein deacetylase, involved in various intracellular processes including suppression of glycolysis and DNA repair. Aldose Reductase (AR), first enzyme of polyol pathway, was proposed to be indirectly associated to these SIRT6 linked processes. Despite these associations, presence of SIRT6 based regulation of AR still remains ambiguous. Thus, regulation of AR expression by SIRT6 was investigated under hyperosmotic stress. A unique model of osmotic stress in U937 cells was used to demonstrate the presence of a potential link between SIRT6 and AR expression. By overexpressing SIRT6 in HeLa cells under hyperosmotic stress, its role on upregulation of AR was revealed. In parallel, increased SIRT6 activity was shown to upregulate AR in U937 cells under hyperosmotic milieu by using pharmacological modulators. Since these modulators also target SIRT1, binding of the inhibitor, Ex-527, specifically to SIRT6 was analyzed in silico. Computational observations indicated that Ex-527 may also target SIRT6 active site residues under high salt concentration, thus, validating in vitro findings. Based on these evidences, a novel regulatory step by SIRT6, modifying AR expression under hyperosmotic stress was presented and its possible interactions with intracellular machinery was discussed.

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Nuclear import of a lipid-modified transcription factor

Cited by 32 publications

References 51 publications

TonEBP/NFAT5 regulates ACTBL2 expression in biomechanically activated vascular smooth muscle cells

TonEBP/NFAT5 regulates ACTBL2 expression in biomechanically activated vascular smooth muscle cells

NFAT5 in cellular adaptation to hypertonic stress – regulations and functional significance

SIRT6 Is a Positive Regulator of Aldose Reductase Expression in U937 and HeLa cells under Osmotic Stress: In Vitro and In Silico Insights

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