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Fumiaki Ohtake, Hikaru Tsuchiya, Keiji Tanaka, Yasushi Saeki
To understand the biological roles of different ubiquitin chains, it is important to determine the types of ubiquitin linkages, the lengths of the polymers, and the combinations of ubiquitin chains attached to substrates. In this chapter, we describe a mass spectrometry-based quantification method of ubiquitin chains, named Ub-AQUA/PRM (ubiquitin-absolute quantification/parallel reaction monitoring), for direct and highly sensitive measurement of the stoichiometry of all eight ubiquitin-ubiquitin linkage types simultaneously...
2019: Methods in Enzymology
Chad A Bousman, Sandra Luza, Serafino G Mancuso, Dali Kang, Carlos M Opazo, Md Shaki Mostaid, Vanessa Cropley, Patrick McGorry, Cynthia Shannon Weickert, Christos Pantelis, Ashley I Bush, Ian P Everall
Dysregulation of the ubiquitin proteasome system (UPS) has been linked to schizophrenia but it is not clear if this dysregulation is detectable in both brain and blood. We examined free mono-ubiquitin, ubiquitinated proteins, catalytic ubiquitination, and proteasome activities in frozen postmortem OFC tissue from 76 (38 schizophrenia, 38 control) matched individuals, as well as erythrocytes from 181 living participants, who comprised 30 individuals with recent onset schizophrenia (mean illness duration = 1 year), 63 individuals with 'treatment-resistant' schizophrenia (mean illness duration = 17 years), and 88 age-matched participants without major psychiatric illness...
February 19, 2019: Scientific Reports
Saba Haq, Soumyadip Das, Dongho Kim, Arun Pandian Chandrasekaran, Seok-Ho Hong, Kye-Seong Kim, Suresh Ramakrishna
RNA-binding protein LIN28A is often highly expressed in human malignant tumors and is involved in tumor metastasis and poor prognosis. Knowledge about post-translational regulatory mechanisms governing LIN28A protein stability and function is scarce. Here, we investigated the role of ubiquitination and deubiquitination on LIN28A protein stability and report that LIN28A protein undergoes ubiquitination. Ubiquitin-specific protease 28 (USP28), a deubiquitinating enzyme, interacts with and stabilizes LIN28A protein to extend its half-life...
December 10, 2018: Biochimica et Biophysica Acta. Molecular Basis of Disease
Connor Arkinson, Viduth K Chaugule, Rachel Toth, Helen Walden
The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability...
October 2018: Life Science Alliance
Lin Hui Chang, Eric R Strieter
Access to well-defined ubiquitin conjugates has been key to elucidating the biochemical functions of proteins in the ubiquitin signaling network. Yet, we have a poor understanding of how deubiquitinases and ubiquitin-binding proteins respond to ubiquitin modifications when anchored to a protein other than ubiquitin or a ubiquitin-like protein. This is due to the difficulty of synthesizing ubiquitinated proteins comprised of native isopeptide bonds. Here we report on the evolution of a deubiquitinase capable of site-specifically modifying itself with defined ubiquitin chains...
September 21, 2018: ACS Chemical Biology
Wuhui Li, Hui Tan, Junmei Liu, Jie Hu, Jialin Cui, Shi Wang, Qingfeng Liu, Fangzhou Hu, Li Ren, Min Tao, Rurong Zhao, Conghui Yang, Qinbo Qin, Shaojun Liu
Spermatogenesis involves a series of cellular transformations and thousands of regulated genes. Previously, we showed that the triploid fish (3nBY) cannot produce mature spermatozoa. In the present study, evaluation of the testis microstructure revealed that germ cells of 3nBY could develop into round spermatids, but then degenerated, resulting in male infertility. In this study we comparatively analysed the testis transcriptomes from 3nBY and its diploid parent YB and identified a series of differentially expressed genes (DEGs) that were enriched in the Wnt signalling pathway and the apoptotic and ubiquitin-mediated proteolysis processes in 3nBY...
August 8, 2018: Reproduction, Fertility, and Development
Annemarie Steiner, Cassandra R Harapas, Seth L Masters, Sophia Davidson
PURPOSE OF REVIEW: The nuclear factor κB (NF-κB) pathway is tightly regulated through multiple posttranslational mechanisms including ubiquitination. Mutations in these regulatory pathways can cause disease and are the focus of this review. RECENT FINDINGS: The linear ubiquitin chain assembly complex (LUBAC) is a trimer made up of HOIL-1L, SHARPIN, and the catalytic subunit HOIP. Loss of function mutations in HOIL-1L and HOIP result in largely overlapping phenotypes, characterized by multi-organ autoinflammation, immunodeficiency, and amylopectinosis...
May 30, 2018: Current Rheumatology Reports
Fan Yang, Yang Xing, Yinan Li, Xiaoning Chen, Jianhai Jiang, Zhilong Ai, Yuanyan Wei
CD133, a widely known marker of cancer stem cells, was recently found in extracellular vesicles. However, the mechanisms underlying CD133 translocation to the extracellular space remain largely unknown. Here we report that CD133 is monoubiquitinated. Ubiquitination occurs primarily on complex glycosylated CD133. The lysine 848 residue at the intracellular carboxyl terminus is one of the sites for CD133 ubiquitination. The K848R mutation does not affect CD133 degradation by the lysosomal pathway but significantly reduces CD133 secretion by inhibiting the interaction between CD133 and tumor susceptibility gene 101 (Tsg101)...
August 1, 2018: Molecular and Cellular Biology
O A Buneeva, A E Medvedev
Proteasomes are large supramolecular protein complexes present in all prokaryotic and eukaryotic cells, where they perform targeted degradation of intracellular proteins. Until recently, it was generally accepted that prior proteolytic degradation in proteasomes the proteins had to be targeted by ubiquitination: the ATP-dependent addition of (typically four sequential) residues of the low-molecular ubiquitin protein, involving the ubiquitin-activating enzyme, ubiquitin-conjugating enzyme and ubiquitin ligase...
March 2018: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
Yueling Zhang, Guicai Gao, Ruihong Lin, Jude Juventus Aweya, Mengyuan Tao, Fan Wang
Although vertebrate immunity has been well studied for the past decades, invertebrate immunity was much less explored. One possible reason was that in vitro culture system was not well established. In this study, Litopenaeus vannamei was applied as an invertebrate study model. Primary culture conditions for L. vannamei hemocytes were optimized to get relatively quiescent state cells. LPS was used as an immune stimulator and the responses of primary cultured hemocytes were transcriptomically analyzed. Our results showed that around 1,600 genes were upregulated and 800 genes were downregulated from LPS treated hemocytes...
May 2018: Fish & Shellfish Immunology
Jiaqi Zhou, Yang Xu, Shaofeng Lin, Yaping Guo, Wankun Deng, Ying Zhang, Anyuan Guo, Yu Xue
Here, we described the updated database iUUCD 2.0 ( for ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin-protein ligases (E3s), deubiquitinating enzymes (DUBs), ubiquitin/ubiquitin-like binding domains (UBDs) and ubiquitin-like domains (ULDs), which act as key regulators in modulating ubiquitin and ubiquitin-like (UB/UBL) conjugations. In total, iUUCD 2.0 contained 136 512 UB/UBL regulators, including 1230 E1s, 5636 E2s, 93 343 E3s, 9548 DUBs, 30 173 UBDs and 11 099 ULDs in 148 eukaryotic species...
January 4, 2018: Nucleic Acids Research
Miranda Thomas, Lawrence Banks
Human Papillomavirus oncoproteins directly target components of the Ubiquitin Proteasome System (UPS) and allow perturbation of multiple cellular processes linked to the control of apoptosis, transcription and innate immunity. This activity primarily creates an environment favourable for viral replication, but can contribute towards malignancy, thus highlighting the roles that manipulation of the UPS can play in the development of human cancers.
October 2017: FEBS Journal
Lizbeth Grimaldo, Alejandro Sandoval, Edgar Garza-López, Ricardo Felix
N-type calcium (CaV2.2) channels are widely expressed in the brain and the peripheral nervous system, where they play important roles in the regulation of transmitter release. Although CaV2.2 channel expression levels are precisely regulated, presently little is known regarding the molecules that mediate its synthesis and degradation. Previously, by using a combination of biochemical and functional analyses, we showed that the complex formed by the light chain 1 of the microtubule-associated protein 1B (LC1-MAP1B) and the ubiquitin-proteasome system (UPS) E2 enzyme UBE2L3, may interact with the CaV2...
2017: PloS One
Martin A Michel, Kirby N Swatek, Manuela K Hospenthal, David Komander
Several ubiquitin chain types have remained unstudied, mainly because tools and techniques to detect these posttranslational modifications are scarce. Linkage-specific antibodies have shaped our understanding of the roles and dynamics of polyubiquitin signals but are available for only five out of eight linkage types. We here characterize K6- and K33-linkage-specific "affimer" reagents as high-affinity ubiquitin interactors. Crystal structures of affimers bound to their cognate chain types reveal mechanisms of specificity and a K11 cross-reactivity in the K33 affimer...
October 5, 2017: Molecular Cell
Kyung Yong Lee, Jun-Sub Im, Etsuko Shibata, Anindya Dutta
Double-strand breaks (DSBs) of DNA in eukaryotic cells are predominantly repaired by non-homologous end joining (NHEJ). The histone chaperone anti-silencing factor 1a (ASF1a) interacts with MDC1 and is recruited to sites of DSBs to facilitate the interaction of phospho-ATM with MDC1 and phosphorylation of MDC1, which are required for the recruitment of RNF8/RNF168 histone ubiquitin ligases. Thus, ASF1a deficiency reduces histone ubiquitination at DSBs, decreasing the recruitment of 53BP1, and decreases NHEJ, rendering cells more sensitive to DSBs...
October 5, 2017: Molecular Cell
Sandrine Cabantous, Ogobara Doumbo, Belco Poudiougou, Laurence Louis, Abdoulaye Barry, Aboubacar A Oumar, Abdoualye Traore, Sandrine Marquet, Alain Dessein
Cerebral malaria, a reversible encephalopathy affecting young children, is a medical emergency requiring urgent clinical assessment and treatment. We performed a whole-transcriptomic analysis of blood samples from Malian children with cerebral or uncomplicated malaria. We focused on transcripts from pathways for which dysfunction has been associated with neurodegenerative disorders. We found that SNCA, SIAH2, UBB, HSPA1A, TUBB2A, and PINK1 were upregulated (fold-increases, ≥2.6), whereas UBD and PSMC5 were downregulated (fold-decreases, ≤4...
September 15, 2017: Journal of Infectious Diseases
Peter K Foote, David T Krist, Alexander V Statsyuk
HECT E3 ubiquitin ligases are responsible for many human disease phenotypes and are promising drug targets; however, screening assays for HECT E3 inhibitors are inherently complex, requiring upstream E1 and E2 enzymes as well as ubiquitin, ATP, and detection reagents. Intermediate ubiquitin thioesters and a complex mixture of polyubiquitin products provide further opportunities for off-target inhibition and increase the complexity of the assay. UbFluor is a novel ubiquitin thioester that bypasses the E1 and E2 enzymes and undergoes direct transthiolation with HECT E3 ligases...
September 14, 2017: Current Protocols in Chemical Biology
Jonathon L Burman, Sarah Pickles, Chunxin Wang, Shiori Sekine, Jose Norberto S Vargas, Zhe Zhang, Alice M Youle, Catherine L Nezich, Xufeng Wu, John A Hammer, Richard J Youle
Within the mitochondrial matrix, protein aggregation activates the mitochondrial unfolded protein response and PINK1-Parkin-mediated mitophagy to mitigate proteotoxicity. We explore how autophagy eliminates protein aggregates from within mitochondria and the role of mitochondrial fission in mitophagy. We show that PINK1 recruits Parkin onto mitochondrial subdomains after actinonin-induced mitochondrial proteotoxicity and that PINK1 recruits Parkin proximal to focal misfolded aggregates of the mitochondrial-localized mutant ornithine transcarbamylase (ΔOTC)...
October 2, 2017: Journal of Cell Biology
Nikhil Panicker, Valina L Dawson, Ted M Dawson
Monogenetic, familial forms of Parkinson's disease (PD) only account for 5-10% of the total number of PD cases, but analysis of the genes involved therein is invaluable to understanding PD-associated neurodegenerative signaling. One such gene, parkin , encodes a 465 amino acid E3 ubiquitin ligase. Of late, there has been considerable interest in the role of parkin signaling in PD and in identifying its putative substrates, as well as the elucidation of the mechanisms through which parkin itself is activated...
August 30, 2017: Biochemical Journal
Evan J Worden, Ken C Dong, Andreas Martin
Poly-ubiquitin chains direct protein substrates to the 26S proteasome, where they are removed by the deubiquitinase Rpn11 during ATP-dependent substrate degradation. Rapid deubiquitination is required for efficient degradation but must be restricted to committed substrates that are engaged with the ATPase motor to prevent premature ubiquitin chain removal and substrate escape. Here we reveal the ubiquitin-bound structure of Rpn11 from S. cerevisiae and the mechanisms for mechanochemical coupling of substrate degradation and deubiquitination...
September 7, 2017: Molecular Cell
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