Sumoylation regulates the transcriptional activity of different human NFAT isoforms in neurons

Vihma, Hanna; Timmusk, Tõnis

doi:10.1016/j.neulet.2017.05.074

Cited by 9 publications

(10 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NFAT1 was found to be rephosphorylated more slowly on its regulatory domain than NFAT4, resulting in prolonged NFAT1 activation and residence in the nucleus 33 . In addition to phosphorylation, NFAT activity can be regulated by protein acetylation 35 , proteolytic cleavage by caspase 3 36 , and SUMOylation by the small ubiquitin-like modifier (SUMO) 37 – 39 . In T cells, SUMOylation of the C termini of NFAT1 and NFAT2 promotes nuclear export of NFAT1 38 and dampens NFAT2-mediated IL-2 transactivation by chromatin condensation 37 , respectively.…”

Section: Activation Of Nfat In Lymphocytesmentioning

confidence: 99%

NFAT control of immune function: New Frontiers for an Abiding Trooper

2018

View full text Add to dashboard Cite

Nuclear factor of activated T cells (NFAT) was first described almost three decades ago as a Ca 2+/calcineurin-regulated transcription factor in T cells. Since then, a large body of research uncovered the regulation and physiological function of different NFAT homologues in the immune system and many other tissues. In this review, we will discuss novel roles of NFAT in T cells, focusing mainly on its function in humoral immune responses, immunological tolerance, and the regulation of immune metabolism.

show abstract

Section: Activation Of Nfat In Lymphocytesmentioning

confidence: 99%

NFAT control of immune function: New Frontiers for an Abiding Trooper

2018

View full text Add to dashboard Cite

show abstract

“…These regulatory serine sites are phosphorylated by different kinases, specifically by PKA, DYRK, CK1, or GSK3 in a hierarchical pattern, creating a complex regulation that may allow for distinctive activation profiles in different cell types [102]. The sumoylation of NFATs, which is cell-specific and AS-isoform-specific, was recently shown to repress the transcriptional activity and regulate its nuclear retention, providing a new regulatory mechanism for NFAT functions [103].…”

Section: Accepted Manuscript 13mentioning

confidence: 99%

Intrinsically Disordered Proteins Link Alternative Splicing and Post-translational Modifications to Complex Cell Signaling and Regulation

Zhou

Zhao

Dunker

2018

Journal of Molecular Biology

View full text Add to dashboard Cite

Intrinsically disordered proteins and regions (IDPs and IDRs) lack well-defined tertiary structures, yet carry out various important cellular functions, especially those associated with cell signaling and regulation. In eukaryotes, IDPs and IDRs contain the preferred loci for both alternative splicing (AS) and many post-translational modifications (PTMs). Furthermore, AS and/or PTMs at these loci generally alter the signaling outcomes associated with these IDPs or IDRs, where the functional cooperation of these three features is named the IDP-AS-PTM toolkit. However, the prevalence of such functional modulations remains unknown. Also, the signal-altering mechanisms by which AS, and PTMs modulate function and the extent to which AS and PTMs collaborate in their signaling modulations have not been well defined for particular protein examples. Here we focus on three important signaling and regulatory IDR-containing protein families in humans, namely, G protein-coupled receptors (GPCRs), which are transmembrane proteins; the nuclear factors of activated T cells (NFATs), which are transcription factors; and the Src family kinases (SFKs), which are signaling enzymes. The goals here are to determine how AS and PTMs individually alter the outcomes of the signaling carried out by the various IDRs and to determine whether AS and PTMs work together to bring about differential cellular responses. We also present data indicating that a wide range of other signaling IDPs or IDRs undergo both AS- and PTM-based modifications, suggesting that they, too, likely take advantage of signal outcome modulations that result from collaboration between these two events. Hence, we propose that the widespread cooperation of IDPs, AS and/or PTMs provides an IDP-AS-PTM toolkit and substantially contributes to the vast complexity of eukaryotic cell signaling systems.

show abstract

“…However, as these two Lys residues have been shown to be SUMOylated (Terui et al, 2004), an alternative plausible explanation is that SUMOylation of NFATc2 on these consensus sites might be necessary for the recognition by its E3 ubiquitinligase. In line with this hypothesis, the protein level of different human NFATc1 and NFATc2 isoforms have been reported to be increased by the double K/R mutation (lysine to arginine substitution) of their C-terminal SUMOylation sites (Vihma & Timmusk, 2017). However, further investigation is required to demonstrate that SUMO indeed plays a role in these effects.…”

Section: Discussionmentioning

confidence: 88%

“…Indeed, effective SUMOylation of NFAT proteins has been described, notably for NFATc1 and NFATc2 (Nayak et al, 2009;Terui et al, 2004). Although the functional consequences of NFAT SUMOylation that have been reported so far are rather related to their nuclear translocation and transactivation activity (E. T. Kim et al, 2019;Nayak et al, 2009;Terui et al, 2004;Vihma & Timmusk, 2017), it might also influence the stability of these proteins. Indeed, Singh et al reported that the double mutation of Lys684 and Lys897 in murine NFATc2 prevents its ubiquitination and degradation induced by zoledronic acid (Singh et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to phosphorylation and ubiquitination, NFAT proteins have been shown to be regulated by SUMOylation. Several studies have shown that covalent conjugation of SUMO to NFATs has an impact on their cytoplasmic-nuclear shuttling, subnuclear localization and transcriptional activity (E. T. Kim et al, 2019;Nayak et al, 2009;Terui et al, 2004;Vihma & Timmusk, 2017). Indeed, SUMOylation can have many consequences on its substrate proteins, including modification of their activity, interaction properties and subcellular localization (Henley et al, 2018;X.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3

Basu-Shrivastava¹,

Mojsa

Mora

et al. 2020

Preprint

View full text Add to dashboard Cite

NFATc3 is the predominant member of the NFAT family of transcription factor in neurons, where it plays a pro-apoptotic role. Mechanisms controlling NFAT protein stability are poorly understood. Here we identify Trim39 as an E3 ubiquitin-ligase of NFATc3. Indeed, Trim39 ubiquitinates NFATc3 in vitro and in cells, whereas silencing of endogenous Trim39 decreases NFATc3 ubiquitination. We also show that Trim17 inhibits Trim39-mediated ubiquitination of NFATc3 by reducing both the E3 ubiquitin-ligase activity of Trim39 and the NFATc3/Trim39 interaction. Moreover, mutation of SUMOylation sites in NFATc3 or SUMO-interacting motif in Trim39 reduces the NFATc3/Trim39 interaction and Trim39-induced ubiquitination of NFATc3. As a consequence, silencing of Trim39 increases the protein level and transcriptional activity of NFATc3, resulting in enhanced neuronal apoptosis. Likewise, a SUMOylation-deficient mutant of NFATc3 exhibits increased stability and pro-apoptotic activity. Taken together, these data indicate that Trim39 modulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for NFATc3.

show abstract

Sumoylation regulates the transcriptional activity of different human NFAT isoforms in neurons

Cited by 9 publications

References 16 publications

NFAT control of immune function: New Frontiers for an Abiding Trooper

NFAT control of immune function: New Frontiers for an Abiding Trooper

Intrinsically Disordered Proteins Link Alternative Splicing and Post-translational Modifications to Complex Cell Signaling and Regulation

Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3

Contact Info

Product

Resources

About