Ubiquitylation within signaling pathways in- and outside of inflammation

2007 ◽  
Vol 97 (03) ◽  
pp. 370-377 ◽  
Author(s):  
Karin Hochrainer ◽  
Joachim Lipp
Keyword(s):  
Signaling Pathways ◽  
26S Proteasome ◽  
Virus Budding ◽  
Polyubiquitin Chains ◽  
Amino Acid Peptide ◽  
Binding Domains ◽  
Ubiquitin Binding ◽  
Different Types ◽  
Lysine Residues ◽  
Ubiquitin Molecule

SummaryUbiquitin is a highly conserved 76-amino-acid peptide that becomes covalently attached to lysine residues of target proteins. Since ubiquitin itself contains seven lysine residues, ubiquitin molecules can generate different types of polyubiquitin chains. Lys48-linked polyubiquitylation is well-known as posttrans-lational tag for targeting proteins for degradation by the 26S proteasome. Recent studies have revealed several new functions of ubiquitin, e.g. activation of protein kinases, control of gene transcription, DNA repair and replication, intracellular trafficking and virus budding. These functions are mainly mediated by Lys63 polyubiquitin chains or attachment of a single ubiquitin molecule to one or several lysine residues within the target protein. Importantly, protein ubiquitylation exhibits inducibility, reversibilty and recognition by specialized ubiquitin-binding domains, features similar to protein phosphorylation. In this review we comprehensively describe regulations of protein ubiquitylation and their impact on distinct signaling pathways.

scholarly journals A novel polyubiquitin chain linkage formed by viral Ubiquitin prevents cleavage by deubiquitinating enzymes

2019 ◽  
Author(s):  
Hitendra Negi ◽  
Pothula Puroshotham Reddy ◽  
Chhaya Patole ◽  
Ranabir Das
Keyword(s):  
Biochemical Properties ◽  
Autographa Californica ◽  
Polyubiquitin Chain ◽  
Deubiquitinating Enzymes ◽  
Polyubiquitin Chains ◽  
Antiviral Responses ◽  
Binding Domains ◽  
Central Helix ◽  
Ubiquitin Binding ◽  
The Stability

ABSTRACTThe Baculoviridae family of viruses encode a viral Ubiquitin gene. Although the viral Ubiquitin is homologous to eukaryotic Ubiquitin (Ub), preservation of this gene in the viral genome indicates a unique function that is absent in the host eukaryotic Ub. We report the structural, biophysical, and biochemical properties of the viral Ubiquitin from Autographa Californica Multiple Nucleo-Polyhedrosis Virus (AcMNPV). The structure of viral Ubiquitin (vUb) differs from Ub in the packing of the central helix α1 to the beta-sheet of the β-grasp fold. Consequently, the stability of the fold is lower in vUb compared to Ub. However, the surface properties, ubiquitination activity, and the interaction with Ubiquitin binding domains are similar between vUb and Ub. Interestingly, vUb forms atypical polyubiquitin chain linked by lysine at the 54th position (K54). The K54-linked polyubiquitin chains are neither effectively cleaved by deubiquitinating enzymes, nor are they targeted by proteasomal degradation. We propose that modification of proteins with the viral Ubiquitin is a mechanism to counter the host antiviral responses.

scholarly journals A novel polyubiquitin chain linkage formed by viral Ubiquitin is resistant to host deubiquitinating enzymes

2020 ◽  
Vol 477 (12) ◽  
pp. 2193-2219
Author(s):  
Hitendra Negi ◽  
Pothula Purushotham Reddy ◽  
Vineeth Vengayil ◽  
Chhaya Patole ◽  
Sunil Laxman ◽  
...  
Keyword(s):  
Viral Genome ◽  
Viral Proteins ◽  
Biochemical Properties ◽  
Autographa Californica ◽  
Polyubiquitin Chain ◽  
Deubiquitinating Enzymes ◽  
Polyubiquitin Chains ◽  
Binding Domains ◽  
Central Helix ◽  
Ubiquitin Binding

The Baculoviridae family of viruses encode a viral Ubiquitin (vUb) gene. Though the vUb is homologous to the host eukaryotic Ubiquitin (Ub), its preservation in the viral genome indicates unique functions that are not compensated by the host Ub. We report the structural, biophysical, and biochemical properties of the vUb from Autographa californica multiple nucleo-polyhedrosis virus (AcMNPV). The packing of central helix α1 to the beta-sheet β1–β5 is different between vUb and Ub. Consequently, its stability is lower compared with Ub. However, the surface properties, ubiquitination activity, and the interaction with Ubiquitin-binding domains are similar between vUb and Ub. Interestingly, vUb forms atypical polyubiquitin chain linked by lysine at the 54th position (K54), and the deubiquitinating enzymes are ineffective against the K54-linked polyubiquitin chains. We propose that the modification of host/viral proteins with the K54-linked chains is an effective way selected by the virus to protect the vUb signal from host DeUbiquitinases.

Properties of natural and artificial proteins displaying multiple ubiquitin-binding domains

2010 ◽  
Vol 38 (1) ◽  
pp. 40-45 ◽  
Author(s):  
Fernando Lopitz-Otsoa ◽  
Manuel S. Rodríguez ◽  
Fabienne Aillet
Keyword(s):  
Effector Proteins ◽  
Target Protein ◽  
Polyubiquitin Chains ◽  
Artificial Proteins ◽  
Binding Domains ◽  
Cellular Factors ◽  
Evolutionary Advantage ◽  
Ubiquitin Binding ◽  
Tandem Ubiquitin Binding Entities

Ubiquitylation provides a rapid alternative to control the activity of crucial cellular factors through the remodelling of a target protein. Diverse ubiquitin chains are recognized by domains with affinity for UBDs (ubiquitin-binding domains) present in receptor/effector proteins. Interestingly, some proteins contain more than one UBD and the preservation of this structure in many species suggests an evolutionary advantage for this topology. Here, we review some typical proteins that naturally contain more than one UBD and emphasize how such structures contribute to the mechanism they mediate. Characteristics such as higher affinities for polyubiquitin chains and chain-linkage preferences can be replicated by the TUBEs (tandem ubiquitin-binding entities). Furthermore, TUBEs show two additional properties: protection of ubiquitylated substrates from deubiquitylating enzymes and interference with the action of the proteasome. Consequently, TUBEs behave as ‘ubiquitin traps’ that efficiently capture endogenous ubiquitylated proteins. Interpretations and hypothetical models proposed by different groups to understand the synchronous action of multiple UBDs are discussed herein.

scholarly journals VWA domain of S5a restricts the ability to bind ubiquitin and Ubl to the 26S proteasome

2014 ◽  
Vol 25 (25) ◽  
pp. 3988-3998 ◽  
Author(s):  
Ravit Piterman ◽  
Ilana Braunstein ◽  
Elada Isakov ◽  
Tamar Ziv ◽  
Ami Navon ◽  
...  
Keyword(s):  
Substrate Binding ◽  
Proteasomal Degradation ◽  
26S Proteasome ◽  
Vast Number ◽  
Binding Domains ◽  
Ubiquitin Binding ◽  
Ubiquitin Receptors

The 26S proteasome recognizes a vast number of ubiquitin-dependent degradation signals linked to various substrates. This recognition is mediated mainly by the stoichiometric proteasomal resident ubiquitin receptors S5a and Rpn13, which harbor ubiquitin-binding domains. Regulatory steps in substrate binding, processing, and subsequent downstream proteolytic events by these receptors are poorly understood. Here we demonstrate that mammalian S5a is present in proteasome-bound and free states. S5a is required for efficient proteasomal degradation of polyubiquitinated substrates and the recruitment of ubiquitin-like (Ubl) harboring proteins; however, S5a-mediated ubiquitin and Ubl binding occurs only on the proteasome itself. We identify the VWA domain of S5a as a domain that limits ubiquitin and Ubl binding to occur only upon proteasomal association. Multiubiquitination events within the VWA domain can further regulate S5a association. Our results provide a molecular explanation to how ubiquitin and Ubl binding to S5a is restricted to the 26S proteasome.

Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

2019 ◽  
Vol 14 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Cong Tang ◽  
Guodong Zhu
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transmembrane Receptors ◽  
Biological Responses ◽  
Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

Probing Affinity and Ubiquitin Linkage Selectivity of Ubiquitin-Binding Domains Using Mass Spectrometry

2012 ◽  
Vol 134 (14) ◽  
pp. 6416-6424 ◽  
Author(s):  
Kleitos Sokratous ◽  
Lucy V. Roach ◽  
Debora Channing ◽  
Joanna Strachan ◽  
Jed Long ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Binding Domains ◽  
Ubiquitin Binding

scholarly journals Poly‐ubiquitin chains paradox: development of novel and selective poly‐ubiquitin binding domains (LB184)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Valerie Brubaker ◽  
Christian Loch ◽  
Kathryn Longenecker ◽  
James Strickler
Keyword(s):  
Binding Domains ◽  
Ubiquitin Binding

Abstract 312: Regulation of Fibrotic Signaling Pathways by Desmosomal Armadillo Proteins in Cardiac Tissue

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Adi D Dubash ◽  
Kathleen J Green
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Cardiac Disease ◽  
Cardiac Tissue ◽  
Cardiac Fibroblasts ◽  
Fibrous Tissue ◽  
Tgf Beta ◽  
Extracellular Matrix Components ◽  
Different Types ◽  
P38mapk Signaling

The process of fibrosis, described as accumulation of myofibroblasts and excessive deposition of extracellular matrix components, is a key development in the progression of multiple different types of cardiac disease. Nevertheless, little is known about the molecular mechanisms which cause the onset of fibrosis in cardiac disease. Fibrosis is a significant component of arrhythmogenic cardiomyopathy (AC), a genetic disorder characterized by replacement of healthy cardiomyocytes (CMs) with fibrous tissue, leading to arrhythmia and in certain cases, sudden death. AC is often characterized as a “disease of the desmosome”, as mutations for all obligate desmosome proteins have been found in cases of AC, including the desmosome armadillo proteins Plakophilin-2 (PKP2) and Plakoglobin (PG). PKP2 and PG are multi-functional proteins involved in both mechanical stabilization of the cardiac area composita, as well as mediation of desmosome-related signaling pathways. We have determined that loss of PKP2 or PG in neonatal CMs causes an aberrant increase in gene expression of pro-fibrotic stimuli such as transforming growth factor beta 1 (TGF-beta1) and Interleukin-6 (IL-6). In addition, p38 MAPK, a known mediator of inflammatory fibrosis, is activated upon loss of PKP2/PG. We hypothesize that mutation or loss of PKP2 or PG cause the recruitment and activation of cardiac fibroblasts via pro-fibrotic TGF-beta and p38MAPK signaling, resulting in pathological fibrosis characteristic of AC. Indeed, conditioned media from PKP2-silenced CMs causes an increase in fibronectin gene expression by freshly isolated cardiac fibroblasts. Our future experiments will investigate whether inhibition of TGF-beta or p38MAPK signaling can alleviate fibrotic gene production. By highlighting a novel link between desmosome armadillo proteins and pro-fibrotic signaling in cardiac tissue, this study provides mechanistic insights into the pathogenesis of AC, as well as advances our knowledge of potential therapeutic targets for combating fibrosis in multiple different types of heart disease or injury.

scholarly journals Binding and Synergizing Motif within Coleopteran Cadherin Enhances Cry3Bb Toxicity on the Colorado Potato Beetle and the Lesser Mealworm

Toxins ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 386 ◽  
Author(s):  
Youngjin Park ◽  
Gang Hua ◽  
Suresh Ambati ◽  
Milton Taylor ◽  
Michael J. Adang
Keyword(s):  
Colorado Potato Beetle ◽  
Diabrotica Virgifera Virgifera ◽  
Reading Frame ◽  
Alphitobius Diaperinus ◽  
Amino Acid Peptide ◽  
Toxin Binding ◽  
High Affinity ◽  
Binding Domains ◽  
Potato Beetle ◽  
Lesser Mealworm

Cry3Bb toxin from Bacillus thuringiensis is an important insecticidal protein due to its potency against coleopteran pests, especially rootworms. Cadherin, a protein in the insect midgut epithelium, is a receptor of Cry toxins; in some insect species toxin-binding domains of cadherins-synergized Cry toxicity. Previously, we reported that the DvCad1-CR8-10 fragment of Diabrotica virgifera virgifera cadherin-like protein (GenBank Accession #EF531715) enhanced Cry3Bb toxicity to the Colorado Potato Beetle (CPB), Leptinotarsa decimlineata (L. decimlineata). We report that individual CR domains of the DvCad1-CR8-10 fragment were found to have strong binding affinities to α-chymotrypsin-treated Cry3Bb. The dissociation constant (Kd) of Cry3Bb binding to the CR8, CR9, and CR10 domain was 4.9 nM, 28.2 nM, and 4.6 nM, respectively. CR8 and CR10, but not CR9, enhanced Cry3Bb toxicity against L. decimlineata and the lesser mealworm Alphitobius diaperinus neonates. In-frame deletions of the DvCad1-CR10 open reading frame defined a high-affinity binding and synergistic site to a motif in residues I1226–D1278. A 26 amino acid peptide from the high affinity Cry3Bb-binding region of CR10 functioned as a Cry3Bb synergist against coleopteran larvae.

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