Small Ubiquitin-like Modifier System Research Articles

SUMO and PIAS repress NF-κB activation in a basal chordate

Small ubiquitin-like modifier (SUMO) regulates various biological processes, including the MyD88/TICAMs-IRAKs-TRAF6-NF-κB pathway, one of the core immune pathways. However, its functions are inconsistent between invertebrates and vertebrates and have rarely been investigated in lower chordates, including amphioxus and fishes. Here, we investigated the SUMOylation gene system in the amphioxus, a living basal chordate. We found that amphioxus has a SUMOylation system that has a complete set of genes and preserves several ancestral traits. We proceeded to study their molecular functions using the mammal cell lines. Both amphioxus SUMO1 and SUMO2 were shown to be able to attach to NF-κB Rel and to inhibit NF-κB activation by 50–75% in a dose-dependent fashion. The inhibition by SUMO2 could be further enhanced by the addition of the SUMO E2 ligase UBC9. In comparison, while human SUMO2 inhibited RelA, human SUMO1 slightly activated RelA. We also showed that, similar to human PIAS1-4, amphioxus PIAS could serve as a SUMO E3 ligase and promote its self-SUMOylation. This suggests that amphioxus PIAS is functionally compatible in human cells. Moreover, we showed that amphioxus PIAS is not only able to inhibit NF-κB activation induced by MyD88, TICAM-like, TRAF6 and IRAK4 but also able to suppress NF-κB Rel completely in the presence of SUMO1/2 in a dose-insensitive manner. This suggests that PIAS could effectively block Rel by promoting Rel SUMOylation. In comparison, in humans, only PIAS3, but not PIAS1/2/4, has been reported to promote NF-κB SUMOylation. Taken together, the findings from amphioxus, together with those from mammals and other species, not only offer insights into the functional volatility of the animal SUMO system, but also shed light on its evolutionary transitions from amphioxus to fish, and ultimately to humans.

Understanding SUMO-mediated adaptive responses in plants to improve crop productivity.

The response to abiotic and biotic stresses in plants and crops is considered a multifaceted process. Due to their sessile nature, plants have evolved unique mechanisms to ensure that developmental plasticity remains during their life cycle. Among these mechanisms, post-translational modifications (PTMs) are crucial components of adaptive responses in plants and transduce environmental stimuli into cellular signalling through the modulation of proteins. SUMOylation is an emerging PTM that has received recent attention due to its dynamic role in protein modification and has quickly been considered a significant component of adaptive mechanisms in plants during stress with great potential for agricultural improvement programs. In the present review, we outline the concept that small ubiquitin-like modifier (SUMO)-mediated response in plants and crops to abiotic and biotic stresses is a multifaceted process with each component of the SUMO cycle facilitating tolerance to several different environmental stresses. We also highlight the clear increase in SUMO genes in crops when compared with Arabidopsis thaliana. The SUMO system is understudied in crops, given the importance of SUMO for stress responses, and for some SUMO genes, the apparent expansion provides new avenues to discover SUMO-conjugated targets that could regulate beneficial agronomical traits.

TCR-Induced Tyrosine Phosphorylation at Tyr270 of SUMO Protease SENP1 by Lck Modulates SENP1 Enzyme Activity and Specificity.

Small ubiquitin-like modifier (SUMO) modification plays an important regulatory role in T cell receptor (TCR) signaling transduction. SUMO-specific proteases (SENPs) have dual-enzyme activities; they can both process SUMO precursors as endopeptidases and participate in SUMO deconjugation as isopeptidases. It remains unclear how the SUMO system, especially SENP1, is regulated by TCR signaling. Here, we show that Lck phosphorylates tyrosine 270 (Y270) of SENP1 upon TCR stimulation, indicating that SENP1 is a substrate of Lck. In vitro endopeptidase activity analysis showed that mutating SENP1 Y270 to either phenylalanine (F) to mimic the phosphorylation-defective state or to glutamate (E) to mimic the negative charge of tyrosine phosphorylation in the enzyme microenvironment did not change its endopeptidase activity towards pre-SUMO1. However, SENP1 Y270E but not Y270F mutation exhibited decreased endopeptidase activity towards pre-SUMO3. Through in vivo isopeptidase activity analysis by rescue expression of SENP1 and its Y270 mutants in a SENP1 CRISPR knockout T cell line, we found that SENP1 Y270F downregulated its isopeptidase activity towards both SUMO1 and SUMO2/3 conjugation by reducing SENP1 binding with sumoylated targets. While overexpression of SENP1 inhibited TCR-induced IL-2 production, overexpression of SENP1 Y270F enhanced it instead. In summary, TCR-induced Y270 phosphorylation of SENP1 may promote its isopeptidase activity and specifically decrease its endopeptidase activity against pre-SUMO3, which finely tunes activation of T cells.

Crosstalk between the chloroplast protein import and SUMO systems revealed through genetic and molecular investigation in Arabidopsis.

The chloroplast proteome contains thousands of different proteins that are encoded by the nuclear genome. These proteins are imported into the chloroplast via the action of the TOC translocase and associated downstream systems. Our recent work has revealed that the stability of the TOC complex is dynamically regulated by the ubiquitin-dependent chloroplast-associated protein degradation pathway. Here, we demonstrate that the TOC complex is also regulated by the small ubiquitin-like modifier (SUMO) system. Arabidopsis mutants representing almost the entire SUMO conjugation pathway can partially suppress the phenotype of ppi1, a pale-yellow mutant lacking the Toc33 protein. This suppression is linked to increased abundance of TOC proteins and improvements in chloroplast development. Moreover, data from molecular and biochemical experiments support a model in which the SUMO system directly regulates TOC protein stability. Thus, we have identified a regulatory link between the SUMO system and the chloroplast protein import machinery.

SUMOylation down-regulates rDNA transcription by repressing expression of upstream-binding factor and proto-oncogene c-Myc

Ribosome biogenesis is critical for proliferating cells and requires the coordinated activities of three eukaryotic RNA polymerases. We recently showed that the small ubiquitin-like modifier (SUMO) system controls the global level of RNA polymerase II (Pol II)-controlled transcription in mammalian cells by regulating cyclin-dependent kinase 9 activity. Here, we present evidence that the SUMO system also plays a critical role in the control of Pol I transcription. Using an siRNA-based knockdown approach, we found that multiple SUMO E3 ligases of the PIAS (protein inhibitor of activated STAT) family are involved in SUMO-mediated repression of ribosomal DNA (rDNA) gene transcription. We demonstrate that endogenous SUMO represses rDNA transcription primarily by repressing upstream-binding factor and proto-oncogene c-Myc expression and that ectopic overexpression of SUMO-associated enzymes additionally represses rDNA transcription via c-Myc SUMOylation and its subsequent degradation. The results of our study reveal a critical role of SUMOylation in the control of rDNA transcription, uncover the underlying mechanisms involved, and indicate that the SUMO system coordinates Pol I- and Pol II-mediated transcription in mammalian cells.

Defining the function of SUMO system in pod development and abiotic stresses in Peanut

BackgroundPosttranslational modification of proteins by small ubiquitin like modifier (SUMO) proteins play an important role during the developmental process and in response to abiotic stresses in plants. However, little is known about SUMOylation in peanut (Arachis hypogaea L.), one of the world’s major food legume crops. In this study, we characterized the SUMOylation system from the diploid progenitor genomes of peanut, Arachis duranensis (AA) and Arachis ipaensis (BB).ResultsGenome-wide analysis revealed the presence of 40 SUMO system genes in A. duranensis and A. ipaensis. Our results showed that peanut also encodes a novel class II isotype of the SCE1, which was previously reported to be uniquely present in cereals. RNA-seq data showed that the core components of the SUMOylation cascade SUMO1/2 and SCE1 genes exhibited pod-specific expression patterns, implying coordinated regulation during pod development. Furthermore, both transcripts and conjugate profiles revealed that SUMOylation has significant roles during the pod development. Moreover, dynamic changes in the SUMO conjugates were observed in response to abiotic stresses.ConclusionsThe identification and organization of peanut SUMO system revealed SUMOylation has important roles during stress defense and pod development. The present study will serve as a resource for providing new strategies to enhance agronomic yield and reveal the mechanism of peanut pod development.

The SUMO System and TGFβ Signaling Interplay in Regulation of Epithelial-Mesenchymal Transition: Implications for Cancer Progression.

Protein post-translational modification by the small ubiquitin-like modifier (SUMO), or SUMOylation, can regulate the stability, subcellular localization or interactome of a protein substrate with key consequences for cellular processes including the Epithelial-Mesenchymal Transition (EMT). The secreted protein Transforming Growth Factor beta (TGFβ) is a potent inducer of EMT in development and homeostasis. Importantly, the ability of TGFβ to induce EMT has been implicated in promoting cancer invasion and metastasis, resistance to chemo/radio therapy, and maintenance of cancer stem cells. Interestingly, TGFβ-induced EMT and the SUMO system intersect with important implications for cancer formation and progression, and novel therapeutics identification.

Exploiting protein modification systems to boost crop productivity: SUMO proteases in focus.

In recent years, post-translational modification (PTM) of proteins has emerged as a key process that integrates plant growth and response to a changing environment. During the processes of domestication and breeding, plants were selected for various yield and adaptational characteristics. The post-translational modifier small ubiquitin-like modifier (SUMO) protein is known to have a role in the regulation of a number of these characteristics. Using bioinformatics, we mined the genomes of cereal and Brassica crops and their non-crop relatives Arabidopsis thaliana and Brachypodium distachyon for ubiquitin-like protease (ULP) SUMO protease sequences. We discovered that the SUMO system in cereal crops is disproportionately elaborate in comparison with that in B. distachyon. We use these data to propose deSUMOylation as a mechanism for specificity in the SUMO system.

The post-translational modification, SUMOylation, and cancer (Review).

SUMOylation is a reversible post-translational modification which has emerged as a crucial molecular regulatory mechanism, involved in the regulation of DNA damage repair, immune responses, carcinogenesis, cell cycle progression and apoptosis. Four SUMO isoforms have been identified, which are SUMO1, SUMO2/3 and SUMO4. The small ubiquitin-like modifier (SUMO) pathway is conserved in all eukaryotes and plays pivotal roles in the regulation of gene expression, cellular signaling and the maintenance of genomic integrity. The SUMO catalytic cycle includes maturation, activation, conjugation, ligation and de-modification. The dysregulation of the SUMO system is associated with a number of diseases, particularly cancer. SUMOylation is widely involved in carcinogenesis, DNA damage response, cancer cell proliferation, metastasis and apoptosis. SUMO can be used as a potential therapeutic target for cancer. In this review, we briefly outline the basic concepts of the SUMO system and summarize the involvement of SUMO proteins in cancer cells in order to better understand the role of SUMO in human disease.

Fifty shades of SUMO: its role in immunity and at the fulcrum of the growth-defence balance.

The sessile nature of plants requires them to cope with an ever-changing environment. Effective adaptive responses require sophisticated cellular mechanisms at the post-transcriptional and post-translational levels. Post-translational modification by small ubiquitin-like modifier (SUMO) proteins is emerging as a key player in these adaptive responses. SUMO conjugation can rapidly change the overall fate of target proteins by altering their stability or interaction with partner proteins or DNA. SUMOylation entails an enzyme cascade that leads to the activation, conjugation and ligation of SUMO to lysine residues of target proteins. In addition to their SUMO processing activities, SUMO proteases also possess de-conjugative activity capable of cleaving SUMO from target proteins, providing reversibility and buffering to the pathway. These proteases play critical roles in the maintenance of the SUMO machinery in equilibrium. We hypothesize that SUMO proteases provide the all-important substrate specificity within the SUMO system. Furthermore, we provide an overview of the role of SUMO in plant innate immunity. SUMOylation also overlaps with multiple growth-promoting and defence-related hormone signalling pathways, and hence is pivotal for the maintenance of the growth-defence balance. This review aims to highlight the intricate molecular mechanisms utilized by SUMO to regulate plant defence and to stabilize the growth-defence equilibrium.

Quantitative high-throughput screening identifies cytoprotective molecules that enhance SUMO conjugation via the inhibition of SUMO-specific protease (SENP)2.

The development of novel neuroprotective treatments for acute stroke has been fraught with failures, which supports the view of ischemic brain damage as a highly complex multifactorial process. Post-translational modifications such as small ubiquitin-like modifier (SUMO)ylation have emerged as critical molecular regulatory mechanisms in states of both homeostasis and ischemic stress, as evidenced by our previous work. Accordingly, the clinical significance of the selective control of the global SUMOylation process has become apparent in studies of ischemic pathobiology and pathophysiology. Herein, we describe a process capable of identifying and characterizing small molecules with the potential of targeting the SUMO system through inhibition of SUMO deconjugation in an effort to develop novel stroke therapies.-Bernstock, J. D., Ye, D., Smith, J. A., Lee, Y.-J., Gessler, F. A., Yasgar, A., Kouznetsova, J., Jadhav, A., Wang, Z., Pluchino, S., Zheng, W., Simeonov, A., Hallenbeck, J. M., Yang, W. Quantitative high-throughput screening identifies cytoprotective molecules that enhance SUMO-conjugation via the inhibition of SUMO-specific protease (SENP)2.

SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling.

The highly conserved NOTCH (neurogenic locus notch homolog protein) signaling pathway functions as a key cell-cell interaction mechanism controlling cell fate and tissue patterning, whereas its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls its signal transduction. Our previous study indicated the potential role of post-translational SUMO (small ubiquitin-like modifier) modification (SUMOylation) in vascular disorders. The aim of this study was to investigate the role of SUMOylation in endothelial NOTCH signaling and angiogenesis. Endothelial SENP1 (sentrin-specific protease 1) deletion, in newly generated endothelial SENP1 (the major protease of the SUMO system)-deficient mice, significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling, as confirmed in cultured endothelial cells. An in vitro SUMOylation assay and immunoprecipitation revealed that when SENP1 associated with N1ICD (NOTCH1 intracellular domain), it functions as a deSUMOylase of N1ICD SUMOylation on conserved lysines. Immunoblot and immunoprecipitation analyses and dual-luciferase assays of natural and SUMO-conjugated/nonconjugated NOTCH1 forms demonstrated that SUMO conjugation facilitated NOTCH1 cleavage. This released N1ICD from the membrane and stabilized it for translocation to the nucleus where it functions as a cotranscriptional factor. Functionally, SENP1-mediated NOTCH1 deSUMOylation was required for NOTCH signal activation in response to DLL4 (Delta-like 4) stimulation. This in turn suppressed VEGF (vascular endothelial growth factor) receptor signaling and angiogenesis, as evidenced by immunoblotted signaling molecules and in vitro angiogenesis assays. These results establish reversible NOTCH1 SUMOylation as a regulatory mechanism in coordinating endothelial angiogenic signaling; SENP1 acts as a critical intrinsic mediator of this process. These findings may apply to NOTCH-regulated biological events in nonvascular tissues and provide a novel therapeutic strategy for vascular diseases and tumors.

The Ubiquitin-Like SUMO System and Heart Function: From Development to Disease.

SUMOylation is a ubiquitin-related transient posttranslational modification pathway catalyzing the conjugation of small ubiquitin-like modifier (SUMO) proteins (SUMO1, SUMO2, and SUMO3) to lysine residues of proteins. SUMOylation targets a wide variety of cellular regulators and thereby affects a multitude of different cellular processes. SUMO/sentrin-specific proteases are able to remove SUMOs from targets, contributing to a tight control of SUMOylated proteins. Genetic and cell biological experiments indicate a critical role of balanced SUMOylation/deSUMOylation for proper cardiac development, metabolism, and stress adaptation. Here, we review the current knowledge about SUMOylation/deSUMOylation in the heart and provide an integrated picture of cardiac functions of the SUMO system under physiologic or pathologic conditions. We also describe potential therapeutic approaches targeting the SUMO machinery to combat heart disease.

Abstract B122: Sumoylation regulates nuclear signaling of ErbB4 intracellular domain

Abstract The members of the ErbB family (EGFR/ErbB1, ErbB2, ErbB3, and ErbB4) of receptor tyrosine kinases (RTK) regulate key cellular processes including proliferation, differentiation, and survival, and play critical roles in several human malignancies. The alternatively spliced ErbB4 JM-a isoform was the first RTK found to signal by a mechanism involving proteolytic release of an intracellular receptor domain (ICD) upon ligand binding. The released ErbB4 ICD can translocate into the nucleus, where it functions as a transcriptional coregulator. ErbB4 ICD has been shown to regulate mammary epithelial development in vivo. Furthermore, nuclear ErbB4 immunoreactivity is frequently observed in clinical breast cancer samples. Although these findings suggest that ErbB4 signaling via ICD is biologically significant, the factors that regulate subcellular distribution and nuclear functions of ErbB4 ICD are largely unknown. We hypothesized that ErbB4 ICD is likely to be regulated by different mechanisms than the ones controlling conventional RTK signaling. One regulatory mechanism that is often employed by nuclear proteins is the small ubiquitin-like modifier (SUMO) system. SUMO proteins modify protein substrates covalently, and alter their function through changes in activity, stability, or subcellular localization. Here, we demonstrate by pull-down and western blotting of cell culture lysates that ErbB4 ICD is modified by SUMO. Full-length ErbB4 was not sumoylated, indicating that SUMO is a specific regulatory modification for the soluble ICD. By using site-directed mutagenesis followed by sumoylation assays, we mapped the major SUMO acceptor site in ErbB4. Wild type and sumoylation deficient mutant of ErbB4 did not differ in their ability to activate canonical RTK signaling pathways downstream of ErbB4. However, fractionation experiments of MCF-7 breast cancer cells showed weaker nuclear targeting of sumoylation deficient mutant compared to wild-type ErbB4 ICD. Protein inhibitor of activated STAT3 (PIAS3), a SUMO E3 ligase that could stimulate the ErbB4 ICD sumoylation, modulated the transcriptional coregulatory activity of ErbB4 ICD in luciferase reporter assays, as well as the function of ErbB4 ICD in HC11 mouse mammary epithelial cell differentiation. Based on these findings we propose that the SUMO system regulates nuclear localization and signaling of ErbB4 ICD. Citation Format: Anna M. Knittle, Maria Sundvall, Katri Vaparanta, Klaus Elenius. Sumoylation regulates nuclear signaling of ErbB4 intracellular domain. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B122.

Mapping the SUMOylated landscape.

SUMOylation is a post‐translational modification that regulates a multitude of cellular processes, including replication, cell‐cycle progression, protein transport and the DNA damage response. Similar to ubiquitin, SUMO (small ubiquitin‐like modifier) is covalently attached to target proteins in a reversible process via an enzymatic cascade. SUMOylation is essential for nearly all eukaryotic organisms, and deregulation of the SUMO system is associated with human diseases such as cancer and neurodegenerative diseases. Therefore, it is of great interest to understand the regulation and dynamics of this post‐translational modification. Within the last decade, mass spectrometry analyses of SUMO proteomes have overcome several obstacles, greatly expanding the number of known SUMO target proteins. In this review, we briefly outline the basic concepts of the SUMO system, and discuss the potential of proteomic approaches to decipher SUMOylation patterns in order to understand the role of SUMO in health and disease.

Abstract A31: Regulation of ErbB4 receptor tyrosine kinase by the SUMO system

Abstract The members of the ErbB family (EGFR/ErbB1, ErbB2, ErbB3, and ErbB4) of receptor tyrosine kinases (RTK) regulate key cellular processes including proliferation, differentiation, and survival, and play critical roles in several human malignancies. The alternatively spliced ErbB4 JM-a isoform was the first RTK found to signal by a mechanism involving proteolytic release of an intracellular receptor domain (ErbB4 ICD). The released ErbB4 ICD can translocate into the nucleus, where it functions as a transcriptional coregulator. ErbB4 ICD has been shown to regulate mammary epithelial development in vivo. Furthermore, nuclear ErbB4 immunoreactivity is frequently observed in clinical breast cancer samples. Although these findings suggest that ErbB4 signaling via ICD is biologically significant, little is known about the regulation of ErbB4 ICD functions or cellular localization. We hypothesized that the soluble ErbB4 ICD is likely to be regulated by different mechanisms than the ones controlling conventional RTK signaling. One regulatory mechanism that is often employed by nuclear proteins is the small ubiquitin-like modifier (SUMO) system. SUMO proteins modify protein substrates covalently, and alter their function through changes in activity, stability, or cellular localization. Here, we demonstrate that ErbB4 ICD is modified by SUMO-1 and SUMO-3. Full-length ErbB4 was not sumoylated, indicating that SUMO is a specific regulatory modification for the soluble ICD. By using site-directed mutagenesis followed by sumoylation assays, we mapped the major SUMO acceptor site in ErbB4. No differences were found between wild type and sumoylation deficient mutant of ErbB4 in biochemical assays measuring the tyrosine kinase activity of ErbB4, or activation of canonical RTK signaling pathways downstream of ErbB4. However, we showed that protein inhibitor of activated STAT3 (PIAS3), a SUMO E3 ligase that could stimulate the sumoylation, modulated the transcriptional coregulatory activity of ErbB4 ICD in luciferase reporter assays, as well as the function of ErbB4 ICD in mammary epithelial cell differentiation. Based on these findings we propose that the SUMO system regulates the nuclear signaling of ErbB4 ICD. Citation Format: Anna Korhonen, Maria Sundvall, Katri Vaparanta, Klaus Elenius. Regulation of ErbB4 receptor tyrosine kinase by the SUMO system. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A31.

Control of Nuclear Activities by Substrate-Selective and Protein-Group SUMOylation

Reversible modification of proteins by SUMO (small ubiquitin-like modifier) affects a large number of cellular processes. In striking contrast to the related ubiquitin pathway, only a few enzymes participate in the SUMO system, although this pathway has numerous substrates as well. Emerging evidence suggests that SUMOylation frequently targets entire groups of physically interacting proteins rather than individual proteins. Protein-group SUMOylation appears to be triggered by recruitment of SUMO ligases to preassembled protein complexes. Because SUMOylation typically affects groups of proteins that bear SUMO-interaction motifs (SIMs), protein-group SUMOylation may foster physical interactions between proteins through multiple SUMO-SIM interactions. Individual SUMO modifications may act redundantly or additively, yet they may mediate dedicated functions as well. In this review, we focus on the unorthodox principles of this pathway and give examples for SUMO-controlled nuclear activities. We propose that collective SUMOylation is typical for nuclear assemblies and argue that SUMO serves as a distinguishing mark for functionally engaged protein fractions.

SUMO and Alzheimer’s Disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and is the most common cause of dementia in the elderly. Histopathologically, AD features insoluble aggregates of two proteins in the brain, amyloid-β (Aβ) and the microtubule-associated protein tau, both of which have been linked to the small ubiquitin-like modifier (SUMO). A large body of research has elucidated many of the molecular and cellular pathways that underlie AD, including those involving the abnormal Aβ and tau aggregates. However, a full understanding of the etiology and pathogenesis of the disease has remained elusive. Consequently, there are currently no effective therapeutic options that can modify the disease progression and slow or stop the decline of cognitive functioning. As part of the effort to address this lacking, there needs a better understanding of the signaling pathways that become impaired under AD pathology, including the regulatory mechanisms that normally control those networks. One such mechanism involves SUMOylation, which is a post-translational modification (PTM) that is involved in regulating many aspects of cell biology and has also been found to have several critical neuron-specific roles. Early studies have indicated that the SUMO system is likely altered with AD-type pathology, which may impact Aβ levels and tau aggregation. Although still a relatively unexplored topic, SUMOylation will likely emerge as a significant factor in AD pathogenesis in ways which may be somewhat analogous to other regulatory PTMs such as phosphorylation. Thus, in addition to the upstream effects on tau and Aβ processing, there may also be downstream effects mediated by Aβ aggregates or other AD-related factors on SUMO-regulated signaling pathways. Multiple proteins that have functions relevant to AD pathology have been identified as SUMO substrates, including those involved in synaptic physiology, mitochondrial dynamics, and inflammatory signaling. Ongoing studies will determine how these SUMO-regulated functions in neurons and glial cells may be impacted by Aβ and AD pathology. Here, we present a review of the current literature on the involvement of SUMO in AD, as well as an overview of the SUMOylated proteins and pathways that are potentially dysregulated with AD pathogenesis.

Overexpression of SENP3 in oral squamous cell carcinoma and its association with differentiation

Small ubiquitin-like modifier (SUMO) modification is an important post-translational protein modification that can be reversed by SUMO-specific proteases (SENPs); however, the physiological function of SENPs remains largely unexplored, and little is known about the regulation of SENPs themselves. As one of the crucial members of the SUMO system, SENP3 is essential for rRNA processing and cell proliferation. In the present study, we analysed the expression of SENP3 in human oral squamous cell carcinoma (OSCC) and investigated the correlation between its expression and clinicopathological parameters in OSCC patients. The expression of SENP3 was higher in OSCC tissues than that in the normal mucosa adjacent to the tumor, and a modest increase in reactive oxygen species (ROS) regulated SENP3 stability and localization. ROS induced SENP3 redistribution from the nucleoli to the nucleoplasm. Taken together, these results indicated that the expression level of SENP3 may be associated with the differentiation of OSCC and that SENP3 may play an important role in the development of OSCC under oxidative stress.

Viral manipulation of cellular protein conjugation pathways: The SUMO lesson

Small ubiquitin-like modifier (SUMO)ylation is a key post-translational modification mechanism that controls the function of a plethora of proteins and biological processes. Given its central regulatory role, it is not surprising that it is widely exploited by viruses. A number of viral proteins are known to modify and/or be modified by the SUMOylation system to exert their function, to create a cellular environment more favorable for virus survival and propagation, and to prevent host antiviral responses. Since the SUMO pathway is a multi-step cascade, viral proteins engage with it at many levels, to advance and favor each stage of a typical infection cycle: replication, viral assembly and immune evasion. Here we review the current knowledge on the interplay between the host SUMO system and viral lifecycle.