Regulation of the nucleocytoplasmic trafficking of viral and cellular proteins by ubiquitin and small ubiquitin‐related modifiers
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Nucleocytoplasmic trafficking of many cellular proteins is regulated by nuclear import/export signals as well as post-translational modifications such as covalent conjugation of ubiquitin and small ubiquitin-related modifiers (SUMOs). Ubiquitination and SUMOylation are rapid and reversible ways to modulate the intracellular localisation and function of substrate proteins. These pathways have been co-opted by some viruses, which depend on the host cell machinery to transport their proteins in and out of the nucleus. In this review, we will summarise our current knowledge on the ubiquitin/SUMO-regulated nuclear/subnuclear trafficking of cellular proteins and describe examples of viral exploitation of these pathways.Keywords:
Deubiquitinating enzyme
SUMO enzymes
Ubiquitins
F-box protein
Post-translational modification (PTM) is a critical and rapid mechanism to regulate all the major cellular processes through the modification of diverse protein substrates. Substrate-specific covalent attachment of ubiquitin and Small Ubiquitin-Like Modifier (SUMO) with the target proteins, known as ubiquitination and SUMOylation, respectively, are crucial PTMs that regulate almost every process in the cell by modulating the stability and fidelity of the proteins. Ubiquitination and SUMOylation play a very significant role to provide tolerance to the plants in adverse environmental conditions by activating/deactivating the pre-existing proteins to a great extent. We reviewed the importance of ubiquitination and SUMOylation in plants, implicating its prospects in various abiotic stress regulations. An exhaustive study of molecular mechanisms of ubiquitination and SUMOylation of plant proteins and their role will contribute to the understanding of physiology underlying mitigation of the abiotic stresses and survival in plants. It will be helpful to strategize the improvement of crops for abiotic stress tolerance.
SUMO enzymes
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Sentrin/small ubiquitin-like modifier (SUMO) is protein modification pathway that regulates multiple biological processes, including cell division, DNA replication/repair, signal transduction, and cellular metabolism. In this review, we will focus on recent advances in the mechanisms of disease pathogenesis, such as cancer, diabetes, seizure, and heart failure, which have been linked to the SUMO pathway. SUMO is conjugated to lysine residues in target proteins through an isopeptide linkage catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes. In steady state, the quantity of SUMO-modified substrates is usually a small fraction of unmodified substrates due to the deconjugation activity of the family Sentrin/SUMO-specific proteases (SENPs). In contrast to the complexity of the ubiquitination/deubiquitination machinery, the biochemistry of SUMOylation and de-SUMOylation is relatively modest. Specificity of the SUMO pathway is achieved through redox regulation, acetylation, phosphorylation, or other posttranslational protein modification of the SUMOylation and de-SUMOylation enzymes. There are three major SUMOs. SUMO-1 usually modifies a substrate as a monomer; however, SUMO-2/3 can form poly-SUMO chains. The monomeric SUMO-1 or poly-SUMO chains can interact with other proteins through SUMO-interactive motif (SIM). Thus SUMO modification provides a platform to enhance protein-protein interaction. The consequence of SUMOylation includes changes in cellular localization, protein activity, or protein stability. Furthermore, SUMO may join force with ubiquitin to degrade proteins through SUMO-targeted ubiquitin ligases (STUbL). After 20 yr of research, SUMO has been shown to play critical roles in most, if not all, biological pathways. Thus the SUMO enzymes could be targets for drug development to treat human diseases.
SUMO enzymes
Deubiquitinating enzyme
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Deubiquitinating enzyme
Proteolysis
Ubiquitins
F-box protein
Ubiquitin-Protein Ligases
Ubiquitin-conjugating enzyme
Protein Degradation
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The Small Ubiquitin-like Modifier 1 (SUMO1) protein is a stress-inducible posttranslational modification present in all eukaryotic organisms. Conjugation of this modifier to a target protein results in the alteration of target protein function. The subsequent de-conjugation of SUMO from target proteins is conducted by a class of enzymes termed SUMO proteases.
Previous research regarding the SUMO E3 ligases SIZ1 and HPY2 has inferred a connection between protein SUMOylation and auxin signalling (Huang, et al., 2009). Here, that connection has been strengthened through phenotypic analysis of Arabidopsis thaliana double knock-out mutant line for the SUMO proteases OVERLY TOLERANT TO SALT 1 and -2 (OTS1 and -2), ots1 ots2, and through the confirmation of the SUMOylation of several auxin cascade proteins.
Loss of OTS1 and -2 was shown to result in an increase in auxin response in Arabidopsis thaliana seedlings exposed to exogenous auxin stimulus, indicating that an increase in global SUMOylation levels alter auxin homeostasis. Further investigation regarding components of the auxin signalling cascade revealed that the auxin receptor, TIR1, and two of the auxin-regulated transcription factors, ARF7 and ARF19, undergo SUMOylation under transient assay conditions. Mutations in TIR1 inducing lysine to arginine substitution of the SUMO-binding residues at each predicted SUMO site eliminated SUMO1 binding under transient assay conditions, further confirming that WT TIR1 is SUMOylated and that the predicted locations were correct. These non-SUMOylatable TIR1 mutant clones were then transformed into the auxin signalling Arabidopsis mutant line tir1/afb2/afb3 to further elucidate the role SUMOylation plays in auxin signalling in planta.
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Deubiquitinating enzyme
F-box protein
Ubiquitin-conjugating enzyme
Ubiquitins
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Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin(-like) protein, and remodel polyubiquitin(-like) chains on target proteins. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five gene families. Most DUB activity is cryptic, and conformational rearrangements often occur during the binding of ubiquitin and/or scaffold proteins. DUBs with specificity for ubiquitin contain insertions and extensions modulating DUB substrate specificity, protein-protein interactions, and cellular localization. Binding partners and multiprotein complexes with which DUBs associate modulate DUB activity and substrate specificity. Quantitative studies of activity and protein-protein interactions, together with genetic studies and the advent of RNAi, have led to new insights into the function of yeast and human DUBs. This review discusses ubiquitin-specific DUBs, some of the generalizations emerging from recent studies of the regulation of DUB activity, and their roles in various cellular processes.
Deubiquitinating enzyme
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SUMO enzymes
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Ubiquitin is a highly conserved small protein that functioned by covalently interact with the lysines on target proteins and forms poly-ubiquitin chains.The small ubiquitin-related modifier(SUMO)also covalently modifies the lysines in target proteins to regulate their localization,stability,interactions and physiological functions.The interaction with single SUMO is predominant,yet it has recently been found that SUMO could also form poly-ubiquitin chains at its inner lysines.Different from single-SUMOylation,proteins with poly-SUMO chains could be further modified by ubiquitin,then targeted for protein degradation.To find out the physiological function in cell growth,differentiation or apoptosis of poly-SUMOylation will be important.This review will introduce the latest researches about poly-SUMOylation.
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Ubiquitins
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SUMO refers to small ubiquitin-like modifier proteins, and SUMOylation is a post-translational modification (PTM) in which SUMO proteins are covalently attached to proteins within the cells. SUMOylation controls the SUMOylated protein functions through its covalent attachment or detachment from proteins. SUMO proteins are composed of ∼100 amino acid residues with an apparent molecular weight of ∼12 kDa. SUMOylation occurs when C-terminal Gly residues of SUMO proteins are linked to the Lys residues of the target proteins. Unlike some ubiquitinated proteins, SUMOylated proteins are not marked for degradation in the proteasome. Attachment and detachment of SUMO proteins to target proteins is involved in many cellular processes including nuclear apoptosis, cytosolic transport, progression through the cell cycle, protein stability, response to stress, transcriptional regulation, etc.
SUMO enzymes
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Ubiquitins
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Deubiquitinating enzymes (DUBs) square measure proteases that cleave ubiquitin or ubiquitin-like proteins from pro-proteins or target proteins. They play many roles within the ubiquitin pathway . First, DUBs perform activation of the ubiquitin pro-proteins, in all probability co-translationally. Ubiquitin is usually expressed as a pro-protein united to either ribosomal proteins or as linear polyubiquitin consisting of multiple copies of mono ubiquitin that has to be processed to yield the mature ubiquitin chemical compound . The polyubiquitin cistron product conjointly contains a further residue at the C-terminus that has to be removed so as to activate ubiquitin
Deubiquitinating enzyme
Ubiquitins
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Ubiquitin-conjugating enzyme
Ribosomal protein
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