How Can Proteins Be Activated, Processed, and Degraded? Give an Example or Describe Each Process.
Trends Pharmacol Sci. Writer manuscript; bachelor in PMC 2022 February ane.
Published in final edited form as:
PMCID: PMC3954851
NIHMSID: NIHMS552860
Regulation of transcription factor activeness past interconnected, post-translational modifications
Theresa M. Filtz
iDepartment of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon 97331
Walter K. Vogel
oneSection of Pharmaceutical Sciences, Oregon State Academy, Corvallis, Oregon 97331
Mark Leid
1Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon 97331
2Department of Integrative Biosciences, Oregon Health & Science University, Portland, Oregon 97239
Abstract
Transcription factors comprise but over vii% of the human proteome and serve every bit the gatekeepers of cellular function, integrating external signal information into cistron expression programs that reconfigure cellular physiology at the nearly basic levels. Surface-initiated, cell signaling pathways converge on transcription factors, decorating these proteins with an array of mail service-translational modifications (PTMs) that are oft interdependent, being linked in time, space, and combinatorial function. These PTMs orchestrate every activeness of a transcription cistron over its entire lifespan—from subcellular localization to protein–poly peptide interactions, sequence-specific Dna binding, transcriptional regulatory action, and protein stability—and play key roles in the epigenetic regulation of gene expression. The multitude of PTMs of transcription factors too offers numerous potential points of intervention for development of therapeutic agents to treat a wide spectrum of diseases. We review PTMs most usually targeting transcription factors, focusing on contempo reports of sequential and linked PTMs of individual factors.
General overview of PTMs of transcription factors
Post-translational modifications regulate every aspect of transcription cistron function and coordinate admission of RNA polymerases to promoter templates. Site-specific, Deoxyribonucleic acid-binding transcription factors (SSTFs) serve to nucleate repressor, activator, enhancer, or silencer complexes and associated enzymatic activities. To coordinate these activities, ofttimes with great spatial, temporal, and tissue-specific precision required of developmental and jail cell-cycle programs, the full range of cellular post-translational modifications (PTMs) of SSTFs may occur. In many cases, these PTMs occur equally private, isolated events and these modifications dictate some aspect of transcription factor function. In other cases, individual PTMs on proteins are sequentially linked—that is, one PTM may promote (or inhibit) the establishment of a second-site PTM within the same protein. These two PTMs are "linked" or "interconnected," and as we draw below, this interconnectedness can exist exploited therapeutically in the handling of illness.
Among the more prominently studied PTMs of transcription factors are phosphorylation, sumoylation, ubiquitination, acetylation, glycosylation, and methylation (Figure ane). The analysis presented beneath (Figure ii) suggests that most of these PTMs occur on transcription factors at about the same charge per unit as seen with other proteins, with the notable exceptions of ubiquitination, glycosylation, and sumoylation, which are institute on transcription factors with moderately decreased, moderately increased and greatly increased frequencies, respectively (Effigy 2). There is no obvious logic why ubiquitination would be somewhat lower or glycosylation somewhat higher among transcription factors. The many-fold increased incidence of sumoylation amidst transcription factors may reflect a real biological miracle. Alternatively, information technology is possible that this modification, which has historically been difficult to find in native proteins, may exist over-represented in transcription factor data sets due to a relative lack of data apropos this modification amid non-nuclear proteins.
Relative enrichment of PTMs in transcription factors
Values are the relative ratio of PTMs identified in human transcription factors compared to those identified in non-transcription factor human proteins and are plotted to evidence the difference from equality for the indicated PTM. Blue confined point the caste of over-enrichment in transcription factors and the red bar indicates the caste of nether-ubiquitination. PTM data was fatigued from the PhosphoSitePlus database [1]. Abbreviations: Ub, ubiquitination; Ac, acetylation; Me, methylation; PO4, phosphorylation; OG, O-GlcNAcylation, and SU, sumoylation.
PTMs may alter SSTF subcellular localization (transport into or out of the nucleus), stability, secondary structure and Deoxyribonucleic acid binding affinity, or third construction and association with co-regulatory factors. PTMs of SSTFs are of particular involvement as a ways of altering transcriptional regulatory activeness of these proteins. Many splendid reviews take focused on the varied effects of transcription gene phosphorylation [ii,3], sumoylation [iv], ubiquitination [5], acetylation [6], and glycosylation [one,seven]. In this review, we provide a few examples of small-mass modifications, including phosphorylation, acetylation, methylation, and glycosylation, and then focus on the larger modifications of sumoylation and ubiquitination, highlighting some examples of interconnected or sequentially-dependent modifications. Specific information about known PTMs of all proteins can exist plant at http://www.phosphosite.org [i–iii] and information about sequentially linked PTMs in proteins tin be accessed at the PTMcode website (http://ptmcode.embl.de) [4,eight]. Both websites are actively curated and exceptionally informative.
Phosphorylation
Phosphorylation is a gateway PTM; easily detected, phosphorylation is often the first PTM to be studied when looking at regulation of protein activity. Rapidly reversible phosphorylation, a ubiquitously utilized mechanism to transduce extracellular signals to the nucleus, may touch transcription factor stability, location, structure and/or protein–interaction network (Figure 3), all of which may impact target gene expression. Phosphorylation may likewise regulate the status of other PTMs in a time-dependent sequence that, for some transcriptional regulatory proteins may culminate in degradation. Straightforward examples of transcription gene regulation past single- or double-site phosphorylation leading to well-characterized, binary furnishings are described elsewhere [2,three,five].
Mechanisms by which PTMs may change transcription factor activity
To change gene expression, phosphorylation may bear upon the secondary structure of a transcription factor (Δ Conformation) to reveal bounden sites or alter affinity, increase or decrease poly peptide degradation (Δ Stability), increase or decrease the nuclear occupancy and thus access to Dna (Localization), alter affinity for DNA regulatory regions (Deoxyribonucleic acid Binding), or alter the modification of the factor by other PTMs including acetylation, sumoylation, methylation, O-GlcNAcylation, or ubiquitination.
Transcription factors may harbor multiple phosphorylation sites, serving as points of convergence of signaling pathways initiating at the plasma membrane. Equally such, transcription factors may office every bit coincidence detectors in which 2 or more pathways must exist activated before gene transcription is contradistinct. For example, TORC2 is normally a cytosolic poly peptide in insulinoma cells that is activated to translocate to the nucleus past dephosphorylation, after which information technology becomes associated with the CREB transcriptional circuitous. TORC2 translocation requires both high glucose and incretin receptor activation to increase intracellular calcium and cAMP levels, respectively. Both calcium-induced activation of calcineurin and inhibition of the SIK2 serine/threonine kinase by campsite are required to mediate TORC2 dephosphorylation at singled-out sites to allow for translocation [2,3,half dozen,9].
Multiple phosphorylation sites may likewise serve every bit tunable bespeak regulators with incremental phosphorylation leading to changes in aamplitude of gene expression. The MSN2 transcription gene in yeast processes unlike stress responses past "tunable" accumulation in the nucleus. Phosphorylation of eight serines clustered within at least ii regulatory domains of MSN2 leads to complex translocation kinetics and differentially tuned responses to stressors. Osmotic stress produces a single pulse of nuclear localization, glucose limitation induces sporadic pulses of nuclear localization, and oxidative stress produces sustained nuclear localization [4,10]. These differential responses are produced by dual regulation of both nuclear import and nuclear export rates by different phosphorylation states of MSN2.
A cooperative signaling response is some other potential role of clusters of multiple phosphorylation sites in an SSTF. Although not a new story, the response of NFAT to dephosphorylation in T cells is the all-time-detailed example of multi-site phosphorylation/dephosphorylation providing a steep response curve for conformational modify in response to signaling (reviewed past [5,11]). Dephosphorylation of NFAT by the calcium-sensitive phosphatase calcineurin allows for nuclear accumulation and transcriptional activity. Nuclear accumulation results from an alteration in the rest between nuclear import and export. Progressive dephosphorylation of xiii phosphorylation sites alters the likelihood that the NFAT nuclear localization betoken subdomain is exposed and that the nuclear export point is hidden due to a phosphorylation-dependent modify in the folding free energy of the protein [6,12,13]. This machinery appears to provide a tightly defined, calcium concentration threshold for activation.
Although the above examples are all of multisite phosphorylation affecting nuclear localization in various means, multisite phosphorylation of SSTFs may take other effects. A multisite phosphorylation gradient progressively impacts the stability and ubiquitination of ATF4 in jail cell cycle command, allowing for ATF4 to exert dose-dependent regulation of target genes in neurogenesis [vii,14]. Dephosphorylation of RUNX1 by the tyrosine phosphatase SHP2 alters RUNX1 poly peptide–protein interactions within the megakaryocyte nucleus, increasing clan with the SWI/SNF chromatin remodeling complex, reducing association with other factors such equally GATA1, and promoting development of megakaryocytes [2,three,15].
O-GlcNAcylation
Many transcription factors, in particular, but also other nuclear proteins, equally well every bit cytosolic proteins are extensively modified by add-on of β-D-N-acetylglucosamine (GlcNAc; Figure 3). The modification of serine and threonine by this monomeric GlcNAc moiety is distinguished from other forms of glycosylation by its relatively small-scale size, subcellular location, and dynamic nature. GlcNAc addition and removal occurs in both the nucleus and cytoplasm, targeting the aforementioned motifs as phosphorylation, with which it competes. This reciprocal regulation is seen both on the nuclear gene substrates and on the enzymes affecting this regulation. Kinases are overrepresented among O-GlcNAcylation substrates [16] and the enzyme responsible for adding GlcNAc is itself phosphoactivated by a kinase that is regulated by O-GlcNAcylation. O-GlcNAcylation of CaMKIV on Ser189 limits phosphoactivation on a nearby Thr200 [7]. Similarly, O-GlcNAcylation of CK2 on Ser347 antagonizes phosphorylation at Thr344 and alters both stability and substrate specificity of the enzyme [17].
Much of the transcriptional proteome is modified past O-GlcNAcylation and the furnishings of this PTM on transcription factors and transcriptional regulatory proteins, including RNA polymerase 2 itself, may be either positive (via poly peptide stabilization) or negative (via inhibition of transcriptional activation) [vii,18,xix].
O-GlcNAcylation occurs equally a event of the activities of the unmarried biosynthetic (O-GlcNAc transferase) and catabolic (O-GlcNAcase) enzymes in this pathway, and the availability of the high-energy donor substrate, UDP-GlcNAc [7]. Flux through the biosynthetic side of the O-GlcNAcylation pathway is dictated by nutrients (glucose), insulin, and cellular stress, and it has been proposed that alterations in the levels O-GlcNAcylation of transcription factors may underlie certain pathological aspects of metabolic diseases, such as diabetes, equally well as neurodegenerative diseases and cancer [7].
Acetylation
Lysine residues are positively charged at physiological pH and acetylation of these residues, which generates an uncharged amide, may logically exist expected to reduce the affinity of the SSTF for DNA. Accordingly, acetylation inhibits interaction of FOXO1 with the glucose-6-phosphatase promoter [20]. Nonetheless, the information testify an evolving picture that is substantially more complex as deacetylation of FOXO1 inhibits its interaction with the BIM promoter in transfected cells [21]. Acetylation of FOXO1 increases its nuclear localization in skeletal muscle, and this results in enhanced regulation of FOXO1 target genes [22]. These findings signal the consequences of alterations in the acetylation status of FOXO1 are both promoter-specific and influenced by prison cell type, highlighting the complication of this relatively unproblematic modification.
Methylation
Arginine methylation may alter the transcriptional regulatory action of SSTFs past altering the poly peptide–interaction network of these factors. For example, methylation of RUNX1 past the arginine methyltransferase PRMT1 inhibits binding of this SSTF to the co-repressor SIN3A and promotes de-repression of RUNX1 target genes [23]. Similarly, methylation of C/EBPβ regulates its interaction with Mediator and SWI/SNF co-activator complexes, and alters C/EBPβ-mediated activation of myeloid and adipogenic target genes [24]. Reversible lysine modification of SSTFs, including NF-κB, STAT3, p53, and pRb, appears to exist catalyzed on promoter templates by the same enzymes that place this modification on and remove it from the core histones [25] The consequence of lysine methylation on the transcriptional regulatory action of these proteins varies with the poly peptide and the context inside the protein [25].
Sumoylation
Reversible modification by small ubiquitin-similar modifier (SUMO) proteins, SUMO1–four, tin greatly affect the activities, nuclear or sub-nuclear localization, and/or the poly peptide–protein interaction network of SSTFs [4,26]. Protein sumoylation couples a glycine residuum in the carboxyl terminus of the activated SUMO poly peptide to the ε-amino group of an acceptor lysine in the target protein, resulting in a covalent, but highly labile, isopeptide bond. The majority of known SUMO-acceptor sites in target proteins arrange to the sequence ψKx(D/E), where ψ corresponds to an aliphatic, hydrophobic amino acid and "x" tin can be whatever amino acid [four,27].
Chiefly, the 10 kDa SUMO moiety is far larger than other common PTMs such as phosphorylation, acetylation, GlcNAc, and methylation, and larger also than ubiquitin. For example, mono-sumoylation of a l kDa transcription gene increases the size, and presumably the surface area, of that gene by 20%. The presence of multiple sites of mono-sumoylation and/or formation of SUMO chains at one or more these sites can easily double the mass and surface expanse of this transcription gene and alter the power of the factor to participate in protein-poly peptide interactions, which play a deterministic role in the activities of SSTFs.
Sumoylation of transcription factors is most oftentimes associated with enhanced transcriptional repressive action [26], and several underlying mechanisms take been described or proposed. Starting time, the presence of a large SUMO moiety may serve as a platform for interaction with proteins containing SUMO interaction motifs (SIMs; reviewed in [28]). Recruitment of the LSD1/CoREST1/HDAC complex to chromatin requires functional interaction of the CoREST1 SIM with SUMO2/3 [29], suggesting that sumoylation of a template-associated factor(s) nucleates assembly of a transcriptionally repressive circuitous. Second, sumoylation plays a primal office in assembly and part of Polycomb group bodies [30], which serve as localized hubs of transcriptional repression [26]. Finally, sumoylation may directly heighten the enzymatic activeness of DNA methylating enzymes, such as DNMT1 [31], which promote transcriptional repression.
Sumoylation stimulates the transcriptional activity of—or at least dampens transcriptional repression mediated by—a handful of transcription factors whose dysregulation has been linked to developmental defects and cancer, merely the underlying mechanisms remain unknown. Sumoylation appears to stimulate transcriptional activation mediated by Ikaros [32], p53 [33], PAX6 [34], and BCL11B [35]. In the latter case, sumoylation of BCL11B results in recruitment of p300 to the BCL11B-NuRD complex and subsequent transcriptional activation of a BCL11B target cistron [35]. Thus, sumoylation of BCL11B serves as a switch that converts BCL11B from a repressor to an activator of transcription, and this has relevance in the T-cell developmental program [35]. Finally, sumoylation of MBD1 inhibits its interaction with the histone-lysine methyltransferase SETDB, impairing repression mediated past the MBD circuitous [36].
Mono-sumoylated transcription factors may be further sumoylated to a land of poly-sumoylation, which may promote subsequent ubiquitination by E3 ligases harboring Due southUMO-Targeted Ubiquitin Ligase (STUbL) action [37,38]. STUbL proteins, such every bit RNF4, harbor multiple SIMs that presumably dock with poly-sumoylated proteins via a multimerized SUMO–SIM interface [39,xl]. STUbL proteins link sumoylation and ubiquitination pathways past catalyzing simultaneous hydrolysis of SUMO adducts and poly-ubiquitination of the target protein, preceding proteosomal degradation (encounter beneath).
Ubiquitination
There are many parallels between protein ubiquitination and sumoylation. Both modifications involve multiple processing steps that produce an agile adduct, which is competent for transfer to target proteins, a reaction carried out by the cognate ligase in each pathway. Although consensus sequences surrounding the signal of attachment diverge, SUMO and ubiquitin moieties share a common linkage to the lysine side chain of substrates [41]. Both SUMO and ubiquitin alter target proteins with a single copy at a unmarried (mono-sumoylation or –ubiquitination) or multiple (multi-mono-sumoylation or –ubiquitination) lysine residues. SUMO and ubiquitin are both capable of concatenation extension at sites of modification, producing poly-sumoylated or –ubiquitinated target proteins [39,42,43]. Sumoylation and ubiquitination change the functional properties of SSTFs in a myriad of overlapping means [42].
Although the role of ubiquitination in poly peptide degradation is well known, ubiquitination contributes to transcriptional processes via both proteolytic and not-proteolytic mechanisms. In general, mono-ubiquitination alters signaling mechanisms and/or activities of SSTFs [42,43]. For example, ubiquitination of FOXO4 drives nuclear translocation and stimulates transcriptional activation mediated by this factor [44]. In this case, ubiquitination may alter the interaction network of the target SSTFs, either by inhibiting basal protein-protein interactions or facilitating those involving ubiquitinated factors with proteins harboring ubiquitin binding domains [43]. In this fashion, ubiquitination likely facilitates nucleation of large protein complexes that are competent for transcriptional activation. Termination of the action of ubiquitinated transcription factors may proceed by at least two pathways. First, the mono-ubiquitinated protein may proceed to go more extensively ubiquitinated, producing a poly-ubiquitinated species, which is then subjected to proteosomal degradation. The kinetics of poly-ubiquitination would presumably dictate the agile lifetime of the ubiquitinated transcription factor circuitous. Second, the ubiquitinated transcription factor may serve as a substrate for de-ubiquitinating enzymes, known as DUBs [45], the availability and catalytic activity of which make up one's mind the active lifetime of the ubiquitinated transcription factor complex.
The role of ubiquitination-induced proteolytic processing of transcription factors is every bit circuitous. Poly-ubiquitination of SSTFs generally promotes deposition via the proteosomal system, and this dictates cellular levels and activities of SSTFs over fourth dimension. Notwithstanding, the corollary is not e'er true: ubiquitination-stimulated proteolysis is necessary for transcriptional activation mediated by several types of SSTFs [46], and recruitment of the proteosomal machinery to the promoter template is integral to the transcriptional activation process [47]. This topic, "activation by destruction," was recently reviewed by Geng and colleagues [42], who suggested that the transcriptional machinery marks particular SSTFs by phosphorylation when these factors are "spent." They further suggested that phosphorylation of spent transcription factors both locks the proteins in an inactive country and recruits the proteosomal machinery to degrade the ubiquitinated transcription gene in situ. This proteolytic action of the ubiquitin-proteosomal system would then facilitate recruitment of non-marked transcription factor to the template for additional rounds of transcription.
Finally, ubiquitination does non necessarily doom transcription factors to the proteosomal organisation and deposition. For example, ubiquitination and subsequent, limited proteolytic processing of NF-κB is required for maturation and activation of this transcription factor (reviewed in [42]).
Interconnected PTMs
PTMs are often progressive with examples of alterations in phosphorylation leading to increased (or decreased) sumoylation, sumoylation leading to ubiquitination through the action of STUbL proteins, phosphorylation affecting acetylation, etc., in kinetically orchestrated sequences over the functional life of the poly peptide. PTMs may also interact reciprocally as well as sequentially. Attempts have been made to quantitate the frequency of multiple, interconnected PTMs in the proteome using sequential isolation techniques and mass spectrometry [48,49]. In these studies, inhibiting the proteasome to reduce ubiquitination altered approximately three% of all phosphorylations. Beltrao et al. used a computational evolutionary approach across the proteomes of 11 eukaryotic species to predict likely interconnected PTMs, and identified regulatory "hot spots" in protein sequences [50]. We provide a few examples of interconnected, transcriptionally relevant PTMs of SSTFs below.
Phosphorylation targets degradation
Absent-minded in quiescent cells but essential for proliferation, c-MYC is regulated by a tight cycle of phosphorylation-driven command of activity and degradation. This cycle starts with ERK-mediated phosphorylation of Ser62, which is essential for transcriptional activity and required for subsequent GSK3-mediated phosphorylation of Thr58 (reviewed by [51]). These phosphorylations orchestrate, both individually and in combination, specific interactions that bring agile c-MYC to target promoters while assuring rapid inactivation and degradation. Efficient association of PIN1, a peptidylprolyl isomerase that catalyzes production of trans-Pro63-MYC, requires Thr58 phosphorylation. This c-MYC conformation speedily moves to target cistron promoters [52] where it specifically recruits transcriptional coactivators and becomes multiply acetylated [53]. Phosphorylation on both sites is required for ubiquitination by AXIN2-scaffolded E3 ligase SCFFbw7, which targets c-MYC for proteosomal degradation. In addition to being more than active, the trans-Pro63 conformation is as well a substrate for trans-directed PP2A-mediated dephosphorylation of phospho-Ser62-MYC, resulting in inactivation of the protein. This normal cycle is disrupted in phosphonegative Thr58 mutants that are ofttimes observed in tumors and result in active phospho-Ser62-MYC accumulation [51].
Deacetylation promotes sumoylation
Competing for the same substrate target lysines, acetylation and sumoylation are competitively antagonist modifications. Regulation of protein sumoylation tin occur through the action of deacetylases, which render the ε-amino groups accessible at sumoylation consensus sites. The tumor suppressor HIC1 is a SSTF required for mammalian evolution and silenced in many tumors. Sumoylation of HIC1 Lys314 is required for transcriptional repressor activity without affecting nuclear or subnuclear localization. Lys314 is also a substrate for acetylation by p300/CBP. Deacetylation of Lys314 past SIRT1 or HDAC4 increases sumoylation and thus the repressor action of the protein [54].
Phosphorylation promotes sumoylation
Phosphorylation regulates the sumoylation and acetylation of some MEF2 proteins. The MEF2 transcription factors are required for myogenesis [55], and neuronal morphogenesis [56]. For MEF2A, MEF2C, and MEF2D, phosphorylation, acetylation and sumoylation are associated with regulation of transcriptional activity in several different tissues [57–59]. For each MEF2 factor, a phosphorylation-dependent sumoylation switch is present with the consensus motif of ψKxExxS/T. This motif is present in other transcription factors [lx], including PPARγ2, HSF, and STAT1. Postsynaptic morphogenesis in cerebellar granule neurons is promoted by sumoylation and inhibited by acetylation of Lys403 of MEF2A. The phosphorylation status of Ser408 plays a key role in the phospho-SUMO switch, and ultimately the transcriptional regulatory activity of MEF2A. Ser408 of MEF2A is phosphorylated under basal or non-stimulated atmospheric condition and this promotes sumoylation at Lys403, which extinguishes the transcriptional activation activity of this gene. Dephosphorylation of phospho-Ser408, which appears to exist catalyzed by the neuronal activity- and calcium-dependent phosphatase calcineurin, promotes a sumoylation to acetylation switch at Lys403, restoring the ability of MEF2A to activate expression of target genes [59].
Similarly to MEF2A, MEF2D sumoylation is dependent upon CDK5-mediated phosphorylation of Ser444 and sumoylation is opposed by calcineurin. Sumoylation of Lys439 of MEF2D inhibits its transcriptional regulatory activity and the ability to potentiate myogenesis. [61].
Phosphorylation-linked desumoylation
The transcriptional regulatory protein BCL11B provides a fascinating example of sequential, linked, and reversible PTMs with a clear transcriptional outcome. BCL11B exists as an ensemble of phosphorylated, sumoylated, and unmodified poly peptide species nether basal conditions in primary mouse thymocytes (Figure 4). The poly peptide becomes rapidly phosphorylated by at least 2 MAP kinases, ERK1/two and p38 [35], immediately following initiation of phorbol ester treatment. Within v minutes all three states of the BCL11B protein collapse into a species that is multiply phosphorylated co-incident with extensive desumoylation of the poly peptide. The latter is due to the presence of a "phospho–deSUMO" switch within the BCL11B protein, the mechanistic basis of which is the phospho-BCL11B-dependent recruitment of SENP1 to the BCL11B circuitous and subsequent hydrolysis of SUMO-BCL11B [35]. Hydrolysis of SUMO-BCL11B is followed by a bicycle of dephosphorylation and re-sumoylation, the latter of which is required for recruitment of the transcriptional co-activator p300 to SUMO-BCL11B complex and subsequent induction of expression of Id2, a factor that is repressed past BCL11B nether basal weather condition [35,62]. Finally, prolonged stimulation results in extensive poly-ubiquitination, perhaps via the action of an unidentified STUbL protein, and proteasomal deposition [35]. This pathway of intricate PTMs appears to serve as a molecular switch that converts the transcriptional repressor BCL11B into an activator of target gene expression, whereas the terminal step of poly-ubiquitination and proteosomal deposition probable serves every bit a mechanism of signal termination.
Sequential regulation of BCL11B past phosphorylation and sumoylation
BCL11B, constitutively in the context of the NuRD repressor circuitous (NuRD), is subject field to modification by kinases, phosphatases (PPTase), sumo-ligating enzymes (UBC9), sumo proteases (SENPx), and sumo-dependent ubiquitin-targeted ligases (StUBL) that modify its activity at the Id2 oncogene promoter over a sixty min time frame following mouse thymocyte stimulation. Termination of the stimulated signal involves ubiquitin-targeted deposition by the proteasome circuitous.
Phosphorylation-linked acetylation and ubiquitination
As described above, FOXO1, a negative regulator of insulin sensitivity [63], is a target for acetylation affecting interaction with target genes. Acetylation also promotes phosphorylation of FOXO1 by the insulin-dependent poly peptide kinase B (PKB)/AKT, rendering a previously acetylated FOXO1 more sensitive to insulin signaling [xx]. Progressive phosphorylation of FOXO1, first by PKB/AKT and and so past CK1, reduces nuclear localization and Deoxyribonucleic acid binding by FOXO1 [64–68], further reducing transcriptional regulatory activity [69]. Phosphorylation of FOXO1 and memory in the cytosol in insulin-sensitive, hepatic cells ultimately leads to its ubiquitination and proteasomal deposition [lxx].
Phosphorylation alters methylation
Prior to activated by extracellular signals C/EBPβ is maintained in a transcriptionally inactive country that is promoted by CARM1-mediated dimethylation of Arg3, which prevents interaction with SWI/SNF and Mediator complexes. MAP kinase-mediated phosphorylation of Thr235 induces a conformational changes that destabilizes CARM1–C/EBPβ interaction. Upon demethylation, C/EBPβ interacts productively with both SWI/SNF and Mediator complexes to induce transcription of target genes [24].
Interconnectedness of PTMs and possible clinical interventions
PTMs tin can be biomarkers of disease states and their utility in assessing and monitoring diseases of misregulation—cancer—is an emerging clinical priority. Our arsenal of clinically useful, PTM-directed drugs are few in full general, and those that impact the PTM condition of SSTFs are fifty-fifty more rare, likely considering most compounds that affect PTMs lack specificity. Notwithstanding, the linkages betwixt PTMs for whatsoever given disease state, once discerned, have the potential to identity novel drug targets. Several real and hypothetical drugs that impact transcription factor PTMs take been described and representative examples of these are summarized in Table ane. Of these, As2Oiii is the one compound that almost obviously targets linked PTMs, and does so on the oncogenic fusion poly peptide PML-RARα [71]. The presence of PML-RARα is causative for acute promyelocytic leukemia, a subtype of acute myeloid leukemia, and the goal of chemotherapy is to eliminate this fusion protein from promyelocytes. EquallyiiO3 binds to the PML portion of the fusion protein and promotes oligomerization with subsequent sumoylation of the fusion protein. In this case, sumoylation of PML-RARα is linked to poly-ubiquitination via the action of the STUbL protein RNF4 [37,38]. Poly-ubiquitinated PML-RARα is then degraded via the proteasome, immigration the jail cell of this oncogenic protein and restoring the differentiative capacity of the affected promyelocytes [40].
Table one
Transcription gene PTMs as therapeutic targets
| PTM afflicted | Target Protein | Potential Use | Comments | Refs |
|---|---|---|---|---|
| | ||||
| Phosphorylation | Tyrosine kinases | Treatment of cancer, rheumatoid arthritis, | Inhibition of tyrosine kinases by drugs, such as imatinib, ruxolitinib, and tofactinib, directly inhibits phosphorylation of STAT proteins, and indirectly inhibits phosphorylation of other transcription factors, including c-JUN, Rb1, Tp73, YAP1, and β-catenin. | [72] |
| Cyclin-dependent kinase v (CDK5) | Type 2 diabetes mellitus | Inhibition of CDK5-mediated phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) may exist useful for T2DM. | [73] | |
| Peptidyl-prolyl cis–trans isomerase NIMA-interacting 1 (PIN1) | Treatment of cancer, including cancer of the breast | PIN1 isomerizes the pSer118–Pro119 bond of estrogen receptor α (ERα), increasing ligand-contained transcriptional activation mediated by ERα and inhibiting proteosomal-dependent degradation of the phospho-activated receptor. PIN1 expression is also elevated in some chest cancers that exhibit poor outcomes and numerous PIN1 inhibitors are in development. | [52,74–76] | |
| Calcineurin (poly peptide phosphatase 3) | Immunosuppressant | Calcineurin action is required to dephosphorylate and promote translocation of the transcription factor NFAT from the cytosol to the nucleus. Inhibition of calcineurin by FK506 (tacrolimus) prevents nuclear translocation of NFAT in T lymphocytes, leading to reduced expression of IL-2 and suppression of adaptive immunity. | [11] | |
| SMAD phosphatases | Spinal cord injury | Phosphorylated members of the SMAD family of transcription factors promote motor neuron axonal outgrowth. Inhibition of SMAD phosphatases may prolong the active lifetime of phospho-SMAD proteins. | [77,78] | |
| | ||||
| Sumoylation | PML-RARα | Acute promyelocytic leukemia | Arsenic Trioxide (Every bit2O3) promotes oligomerization and sumoylation of the PML portion of the PML- RARα fusion protein, with subsequent ubiquitination of the protein via SUMO-targeted ubiquitin ligases (STUbL proteins) and proteosomal deposition. | [71] |
| SENP proteins | Treatment of cancer | Inhibition of SENP proteins by betulinic acid and related compounds may prolong the lifetime of sumoylated transcription factors, such as SP1. | [79,80] | |
| | ||||
| Ubiquitination | p53 | Treatment of cancer | Compounds such equally Nutlin-3 bind to the MDM2 binding pocket of p53, inhibiting p53-MDM2 interaction and MDM2-mediated ubiquitination of p53, and prolonging the lifetime of activated p53. | [81] |
| | ||||
| Methylation | Co-activator-associated arginine methyltransferase 1 (CARM1) | Treatment of cancer, potentially other disorders | Indole and/or pyazole inhibitors of the catalytic part of CARM1 may interrupt signaling by estrogen receptors in breast cancer, or other transcription factors in other hormone-dependent tumors. | [82,83] |
| | ||||
| O-GlcNAcylation | O-GlcNAc transferase (OGT) | Handling of cancer; particularly of the breast | Inhibition of OGT may sensitize chest cancer cells to tamoxifen therapy. | [84] |
| O-GlcNAc hydrolase (O-GlcNAcase) | As however unknown | Inhibition of O-GlcNAcase past compounds, such equally Thiamet-G, may exist a means of altering the O- GlcNAc/phosphorylation reciprocal balance toward O-GlcNAc. This may serve to turn off transcription factors that require phosphorylation for activity. A similar observation has been made in the example of Tau kinases, which get hyperphosphorylated in Alzheimer'southward disease and drive tau-mediated neurodegeneration. | [85,86] | |
| | ||||
| Acetylation | Histone acetyltransferases (HATs) | Treatment of cancer, HIV | Garcinol, a natural compound, inhibits HAT activeness of p300/CBP and may be useful to reprogram histone and transcription gene modifications that are characteristic of illness processes, such as cancer and HIV. | [87,88] |
Concluding remarks
Although the evidence is merely beginning to accrue on the frequency of multiply-modified proteins, information technology seems likely that evolving techniques, such as highly sensitive and quantitative mass spectrometry, will undercover many more examples. Multiple PTMs expand the possibilities for scalable transcriptional regulatory action, and sequential, interdependent modifications allow for time-dependent command of gene expression in response to an initial stimulus with downstream furnishings that may play out over an extended time frame. Owing to the great importance of mail service-translational modification in dictating every aspect of transcription factor part and the key role that these proteins play in illness, it is perhaps not surprising that PTMs of transcription factors accept become an attractive target for the development of therapeutic agents to care for a wide diverseness of diseases. Table i provides representative examples of electric current and future drug classes that target various transcription gene PTMs.
Acknowledgments
The authors give thanks Marking Zabriskie for chemic structures, and Richard Hibbert for graphic design of the figures. This piece of work was supported in part by the National Institutes of General Medical Sciences (grant GM096243 to T. Yard. F.) and Dental and Craniofacial Research (grant DE021879 to M. L.) of the National Institutes of Health.
Footnotes
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954851/
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