scholarly journals Pax8 protein stability is controlled by sumoylation

2008 ◽  
Vol 42 (1) ◽  
pp. 35-46 ◽  
Author(s):  
Tiziana de Cristofaro ◽  
Anna Mascia ◽  
Andrea Pappalardo ◽  
Barbara D'Andrea ◽  
Lucio Nitsch ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Critical Role ◽  
Nuclear Bodies ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Signal Transducers ◽  
Protein Protein Interaction ◽  
Sumo Ligase ◽  
Development And Differentiation ◽  
Substitution Mutant

The transcription factor Pax8 is involved in the morphogenesis of the thyroid gland and in the maintenance of the differentiated thyroid phenotype. Despite the critical role played by Pax8 during thyroid development and differentiation, very little is known of its post-translational modifications and how these modifications may regulate its activity. We focused our attention on the study of a specific post-translational modification, i.e., sumoylation. Sumoylation is a dynamic and reversible process regulating gene expression by altering transcription factor stability, protein–protein interaction and subcellular localization of target proteins. The analysis of Pax8 protein sequence revealed the presence of one sumoylation consensus motif (ψKxE), strongly conserved among mammals, amphibians, and fish. We demonstrated that Pax8 is sumoylated by the addition of a single small ubiquitin-like modifier (SUMO) molecule on its lysine residue 309 and that Pax8K309R, a substitution mutant in which the candidate lysine is replaced with an arginine, is no longer modified by SUMO. In addition, we analyzed whether protein inhibitor of activated signal transducers and activators of transcription (PIASy), a member of the PIAS STAT family of proteins, could function as a SUMO ligase and we demonstrated that indeed PIASy is able to increase the fraction of sumoylated Pax8. Interestingly, we show that Pax8 is targeted in the SUMO nuclear bodies, which are structures that regulate the nucleoplasmic concentration of transcription factors by SUMO trapping. Finally, we report here that the steady-state protein level of Pax8 is controlled by sumoylation.

scholarly journals PIAS1 potentiates the anti-EBV activity of SAMHD1 through SUMOylation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Farjana Saiada ◽  
Kun Zhang ◽  
Renfeng Li
Keyword(s):  
Lytic Replication ◽  
Dependent Manner ◽  
Dna Viruses ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Barr Virus ◽  
Sumo Ligase ◽  
Lysine Residues ◽  
Epstein Barr ◽  
Rna And Dna

Abstract Background Sterile alpha motif and HD domain 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase (dNTPase) that restricts the infection of a variety of RNA and DNA viruses, including herpesviruses. The anti-viral function of SAMHD1 is associated with its dNTPase activity, which is regulated by several post-translational modifications, including phosphorylation, acetylation and ubiquitination. Our recent studies also demonstrated that the E3 SUMO ligase PIAS1 functions as an Epstein-Barr virus (EBV) restriction factor. However, whether SAMHD1 is regulated by PIAS1 to restrict EBV replication remains unknown. Results In this study, we showed that PIAS1 interacts with SAMHD1 and promotes its SUMOylation. We identified three lysine residues (K469, K595 and K622) located on the surface of SAMHD1 as the major SUMOylation sites. We demonstrated that phosphorylated SAMHD1 can be SUMOylated by PIAS1 and SUMOylated SAMHD1 can also be phosphorylated by viral protein kinases. We showed that SUMOylation-deficient SAMHD1 loses its anti-EBV activity. Furthermore, we demonstrated that SAMHD1 is associated with EBV genome in a PIAS1-dependent manner. Conclusion Our study reveals that PIAS1 synergizes with SAMHD1 to inhibit EBV lytic replication through protein–protein interaction and SUMOylation.

scholarly journals Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation

2021 ◽  
Vol 11 ◽  
Author(s):  
Carolina Alquezar ◽  
Shruti Arya ◽  
Aimee W. Kao
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Protein Localization ◽  
Critical Role ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Tau Function ◽  
Potential Impact ◽  
Important Position

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information on potential and observed PTMs on tau provides an opportunity to better understand these modifications in the context of tau homeostasis, which becomes perturbed with aging and disease. Prevailing views regard tau as a protein that undergoes abnormal phosphorylation prior to its accumulation into the toxic aggregates implicated in Alzheimer's disease (AD) and other tauopathies. However, the phosphorylation of tau may, in fact, represent part of the normal but interrupted function and catabolism of the protein. In addition to phosphorylation, tau undergoes another forms of post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, and nitration. A holistic appreciation of how these PTMs regulate tau during health and are potentially hijacked in disease remains elusive. Recent studies have reinforced the idea that PTMs play a critical role in tau localization, protein-protein interactions, maintenance of levels, and modifying aggregate structure. These studies also provide tantalizing clues into the possibility that neurons actively choose how tau is post-translationally modified, in potentially competitive and combinatorial ways, to achieve broad, cellular programs commensurate with the distinctive environmental conditions found during development, aging, stress, and disease. Here, we review tau PTMs and describe what is currently known about their functional impacts. In addition, we classify these PTMs from the perspectives of protein localization, electrostatics, and stability, which all contribute to normal tau function and homeostasis. Finally, we assess the potential impact of tau PTMs on tau solubility and aggregation. Tau occupies an undoubtedly important position in the biology of neurodegenerative diseases. This review aims to provide an integrated perspective of how post-translational modifications actively, purposefully, and dynamically remodel tau function, clearance, and aggregation. In doing so, we hope to enable a more comprehensive understanding of tau PTMs that will positively impact future studies.

scholarly journals The Roles of Post-Translational Modifications in STAT3 Biological Activities and Functions

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 956
Author(s):  
Annachiara Tesoriere ◽  
Alberto Dinarello ◽  
Francesco Argenton
Keyword(s):  
Transcription Factor ◽  
Cancer Progression ◽  
Transcriptional Activity ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Cellular Models ◽  
Stat3 Phosphorylation ◽  
Cellular Context ◽  
Cell Growth And Proliferation

STAT3 is an important transcription factor that regulates cell growth and proliferation by regulating gene transcription of a plethora of genes. This protein also has many roles in cancer progression and several tumors such as prostate, lung, breast, and intestine cancers that are characterized by strong STAT3-dependent transcriptional activity. This protein is post-translationally modified in different ways according to cellular context and stimulus, and the same post-translational modification can have opposite effects in different cellular models. In this review, we describe the studies performed on the main modifications affecting the activity of STAT3: phosphorylation of tyrosine 705 and serine 727; acetylation of lysine 49, 87, 601, 615, 631, 685, 707, and 709; and methylation of lysine 49, 140, and 180. The extensive results obtained by different studies demonstrate that post-translational modifications drastically change STAT3 activities and that we need further analysis to properly elucidate all the functions of this multifaceted transcription factor.

scholarly journals A post-translational modification of the sheath modulatesFrancisellatype VI secretion system assembly and function

2018 ◽  
Author(s):  
Jason Ziveri ◽  
Cerina Chhuon ◽  
Anne Jamet ◽  
Guénolé Prigent ◽  
Héloïse Rytter ◽  
...  
Keyword(s):  
Critical Role ◽  
Phosphorylation Site ◽  
Post Translational Modification ◽  
Secretion Systems ◽  
Post Translational Modifications ◽  
Type Vi Secretion ◽  
Sheath Formation ◽  
Canonical Type ◽  
The Stability ◽  
And Function

AbstractFrancisella tularensisis a facultative intracellular pathogen that causes the zoonotic disease tularemia in human and animal hosts. This bacterium possesses a non-canonical type VI secretion systems (T6SS) required for phagosomal escape and access to its replicative niche in the cytosol of infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the Francisella T6SS in culture. We found that the amounts of essentially all the TSS6 proteins remained unchanged upon KCl stimulation. We therefore hypothesized that a post-translational modification might be involved in T6SS assembly. A whole cell phosphoproteomic analysis allowed us to identify a unique phosphorylation site on IglB, the TssC homologue and key component of the T6SS sheath. Importantly, the phosphorylated form of IglB was not present in the contracted sheath and 3D modeling indicated that the charge repulsion provoked by addition of a phosphogroup on tyrosine 139 was likely to weaken the stability of the sheath structure. Substitutions of the phosphorylatable residue of IglB (tyrosine 139) with alanine or with phosphomimetics prevented T6SS formation and totally impaired phagosomal escape. In contrast, the substitution with the non-phosphorylatable aromatic analog phenylalanine impaired but did not prevent phagosomal escape and cytosolic bacterial multiplication in J774-1 macrophages. Altogether these data suggest that phosphorylation of the sheath participates to T6SS disassembly. Post-translational modifications of the sheath may represent a previously unrecognized mechanism to finely modulate the dynamics of T6SS assembly-disassembly.Data are available via ProteomeXchange with identifier PXD012507.SynopsisFrancisellapossesses a non-canonical T6SS that is essential for efficient phagosomal escape and access to the cytosol of infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the Francisella T6SS in culture. We found that KCl stimulation did not result in an increased production of TSS6 proteins. We therefore hypothesized that a post-translational modification might be involved in T6SS assembly. Using a global and site-specific phosphoproteomic analysis ofFrancisellawe identified a unique phosphorylation site on IglB, the TssC homologue and a key component of the T6SS contractile sheath. We show that this site plays a critical role in T6SS biogenesis and propose that phosphorylation may represent a new mechanism affecting the dynamics of sheath formation.

Abstract O-2: The Role of Post-translational Modifications in SERCA2a-related Cardiac Dysfunction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Changwon Kho ◽  
Dongtak Jeong ◽  
Ahyoung Lee ◽  
Shinichi Mitsuyama ◽  
Jae Gyun Oh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Critical Role ◽  
Hdac Inhibitors ◽  
Post Translational Modification ◽  
Mice Model ◽  
Down Regulation ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Post Translational Modifications ◽  
Lysine Residues ◽  
Interfering Rna

The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) has become a validated target for the treatment of heart failure (HF). The relationship between reduced SERCA2a activity and decreases in protein expression in the setting of HF has been found to be non-linear and the toxic intracellular milieu in HF contributes to SERCA2a’s dysfunction. Post-translational modification (PTM) of SERCA2a has been recently described to as an important mechanism that can explain a reduction in SERCA2a activity in HF. Based on a comprehensive proteomic analysis, we found that the levels and activity of SERCA2a in cardiomyocytes are modulated in parallel with the levels of small ubiquitin-like modifier type 1 (SUMO-1). Moreover, our work has shown that SUMO-1 plays a critical role in protecting SERCA2a from pathological conditions (Kho et al, Nature, 2011). More recently, we demonstrated that SUMO-1 gene transfer and its combination with SERCA2a led to a reversal of HF in a porcine model of ischemic induced HF (Tilemann et al, Sci Transl Med, 2013). In our analysis of SERCA2a PTM in animal models of HF, we observed that SERCA2a is acetylated, and that this acetylation is more prominent in failing hearts. The acetylation of SERCA2a was validated by acetylation assays with acetyltransferase and HDAC inhibitors. We identified several lysine residues on SERCA2a for susceptible to acetylation. In addition, we found that Sirt1 enzyme deacetylates SERCA2a. Sirt1 down-regulation in HL-1 cells using small interfering RNA increased SERCA2a acetylation and thereby decreased its activity. Moreover, SERCA2a acetylation was increased when Sirt1 was depleted by recombinant adeno-associated virus carrying short hairpin RNA for Sirt1 in mice model, which reflected a decrease in intensity of interaction between Sirt1 and SERCA2a. Reduced acetylation was accompanied by an increase in SERCA2a SUMOylation in the heart. Decreased acetylation, combined with increased SUMOylation, of SERCA2a may contribute to the cardioprotective effects of Sirt1. Our results show that SERCA2a acetylation increases during HF and negatively impacts SERCA2a’s function, suggesting that the down-regulation of SERCA2a acetylation may afford a novel intervention in the setting of heart failure.

scholarly journals Critical Role for Lysine 685 in Gene Expression Mediated by Transcription Factor Unphosphorylated STAT3

2014 ◽  
Vol 289 (44) ◽  
pp. 30763-30771 ◽  
Author(s):  
Maupali Dasgupta ◽  
Hamiyet Unal ◽  
Belinda Willard ◽  
Jinbo Yang ◽  
Sadashiva S. Karnik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Transcription Factor ◽  
Growth Factors ◽  
Critical Role ◽  
Minor Role ◽  
Post Translational Modifications ◽  
New Information ◽  
Phosphorylated Stat3

STAT3 is a pleiotropic transcription factor that is activated by the phosphorylation of tyrosine 705 in response to many cytokines and growth factors. STAT3 without Tyr-705 phosphorylation (U-STAT3) is also a potent transcription factor, and its concentration in cells increases greatly in response to STAT3 activation because the STAT3 gene can be driven by phosphorylated STAT3 dimers. We have now searched for post-translational modifications of U-STAT3 that might have a critical role in its function. An analysis by mass spectroscopy indicated that U-STAT3 is acetylated on Lys-685, and the integrity of Lys-685 is required for the expression of most U-STAT3-dependent genes. In contrast, we found only a very minor role for Lys-685 in gene expression induced in response to tyrosine-phosphorylated STAT3. U-STAT3 plays an important role in angiotensin II-induced gene expression and in the consequent development of cardiac hypertrophy and dysfunction. Mutation of Lys-685 inhibits this function of STAT3, providing new information on the role of U-STAT3 in augmenting the development of heart failure.

Reading the phosphorylation code: binding of the 14-3-3 protein to multivalent client phosphoproteins

2020 ◽  
Vol 477 (7) ◽  
pp. 1219-1225 ◽  
Author(s):  
Nikolai N. Sluchanko
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Major Protein ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Biochemical Journal ◽  
Multiple Binding ◽  
And Control

Many major protein–protein interaction networks are maintained by ‘hub’ proteins with multiple binding partners, where interactions are often facilitated by intrinsically disordered protein regions that undergo post-translational modifications, such as phosphorylation. Phosphorylation can directly affect protein function and control recognition by proteins that ‘read’ the phosphorylation code, re-wiring the interactome. The eukaryotic 14-3-3 proteins recognizing multiple phosphoproteins nicely exemplify these concepts. Although recent studies established the biochemical and structural basis for the interaction of the 14-3-3 dimers with several phosphorylated clients, understanding their assembly with partners phosphorylated at multiple sites represents a challenge. Suboptimal sequence context around the phosphorylated residue may reduce binding affinity, resulting in quantitative differences for distinct phosphorylation sites, making hierarchy and priority in their binding rather uncertain. Recently, Stevers et al. [Biochemical Journal (2017) 474: 1273–1287] undertook a remarkable attempt to untangle the mechanism of 14-3-3 dimer binding to leucine-rich repeat kinase 2 (LRRK2) that contains multiple candidate 14-3-3-binding sites and is mutated in Parkinson's disease. By using the protein-peptide binding approach, the authors systematically analyzed affinities for a set of LRRK2 phosphopeptides, alone or in combination, to a 14-3-3 protein and determined crystal structures for 14-3-3 complexes with selected phosphopeptides. This study addresses a long-standing question in the 14-3-3 biology, unearthing a range of important details that are relevant for understanding binding mechanisms of other polyvalent proteins.

Dicarbonyl derived post-translational modifications: chemistry bridging biology and aging-related disease

2020 ◽  
Vol 64 (1) ◽  
pp. 97-110
Author(s):  
Christian Sibbersen ◽  
Mogens Johannsen
Keyword(s):  
Mass Spectrometry ◽  
Future Research ◽  
Amino Acid Residues ◽  
Post Translational Modification ◽  
Dicarbonyl Compounds ◽  
Protein Targets ◽  
Post Translational Modifications ◽  
Reactive Protein ◽  
Glycation End Products ◽  
Direct Mass Spectrometry

Abstract In living systems, nucleophilic amino acid residues are prone to non-enzymatic post-translational modification by electrophiles. α-Dicarbonyl compounds are a special type of electrophiles that can react irreversibly with lysine, arginine, and cysteine residues via complex mechanisms to form post-translational modifications known as advanced glycation end-products (AGEs). Glyoxal, methylglyoxal, and 3-deoxyglucosone are the major endogenous dicarbonyls, with methylglyoxal being the most well-studied. There are several routes that lead to the formation of dicarbonyl compounds, most originating from glucose and glucose metabolism, such as the non-enzymatic decomposition of glycolytic intermediates and fructosyl amines. Although dicarbonyls are removed continuously mainly via the glyoxalase system, several conditions lead to an increase in dicarbonyl concentration and thereby AGE formation. AGEs have been implicated in diabetes and aging-related diseases, and for this reason the elucidation of their structure as well as protein targets is of great interest. Though the dicarbonyls and reactive protein side chains are of relatively simple nature, the structures of the adducts as well as their mechanism of formation are not that trivial. Furthermore, detection of sites of modification can be demanding and current best practices rely on either direct mass spectrometry or various methods of enrichment based on antibodies or click chemistry followed by mass spectrometry. Future research into the structure of these adducts and protein targets of dicarbonyl compounds may improve the understanding of how the mechanisms of diabetes and aging-related physiological damage occur.

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