Xiaohong Zhou, Christina Monnie, Maria DeLucia, Jinwoo Ahn
BACKGROUND: Vpr is a virion-associated protein that is encoded by lentiviruses and serves to counteract intrinsic immunity factors that restrict infection. HIV-1 Vpr mediates proteasome-dependent degradation of several DNA repair/modification proteins. Mechanistically, Vpr directly recruits cellular targets onto DCAF1, a substrate receptor of Cullin 4 RING E3 ubiquitin ligase (CRL4) for poly-ubiquitination. Further, Vpr can mediate poly-ubiquitination of DCAF1-interacting proteins by the CRL4...
March 1, 2021: Virology Journal
Ya-Ching Fang, Ssu-Ju Fu, Po-Hao Hsu, Pei-Tzu Chang, Jing-Jia Huang, Yi-Chih Chiu, Yi-Fan Liao, Guey-Mei Jow, Chih-Yung Tang, Chung-Jiuan Jeng
Mutations in the human gene encoding the neuron-specific Eag1 voltage-gated K+ channel are associated with neurodevelopmental diseases, indicating an important role of Eag1 during brain development. A disease-causing Eag1 mutation is linked to decreased protein stability that involves enhanced protein degradation by the E3 ubiquitin ligase cullin 7 (CUL7). The general mechanisms governing protein homeostasis of plasma membrane- and endoplasmic reticulum (ER)-localized Eag1 K+ channels, however, remains unclear...
February 26, 2021: Journal of Biological Chemistry
Yifan Chen, Xuejing Shao, Ji Cao, Hong Zhu, Bo Yang, Qiaojun He, Meidan Ying
Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors...
February 2021: Acta Pharmaceutica Sinica. B
Yuxing Wang, Xiaohua Pan, Yanjun Li, Ru Wang, Yuanyuan Yang, Baichun Jiang, Gongping Sun, Changshun Shao, Molin Wang, Yaoqin Gong
Tamoxifen (TAM) resistance is a significant clinical challenge in endocrine therapies for estrogen receptor (ER)-positive breast cancer patients. Cullin 4B (CUL4B), which acts as a scaffold protein in CUL4B-RING ubiquitin ligase complexes (CRL4B), is frequently overexpressed in cancer and represses tumor suppressors through diverse epigenetic mechanisms. However, the role and the underlying mechanisms of CUL4B in regulating drug resistance remain unknown. Here, we showed that CUL4B promotes TAM resistance in breast cancer cells through a miR-32-5p/ER-α36 axis...
February 27, 2021: Journal of Pathology
Xiaoyu Zhang, Marvin Thielert, Haoxin Li, Benjamin F Cravatt
DCAF16 is a substrate recognition component of Cullin-RING E3 ubiquitin ligases that can be targeted by electrophilic PROTACs (proteolysis targeting chimeras) to promote the nuclear-restricted degradation of proteins. The endogenous protein substates of DCAF16 remain unknown. In this study, we compared the protein content of DCAF16-wild type and DCAF16-knockout (KO) cells by untargeted mass spectrometry-based proteomics, identifying the Tudor domain-containing protein Spindlin-4 (SPIN4) as a protein with a level that was substantially increased in cells lacking DCAF16...
February 26, 2021: Biochemistry
Maoxiao Feng, Yunshan Wang, Lei Bi, Pengju Zhang, Huaizhi Wang, Zhongxi Zhao, Jian-Hua Mao, Guangwei Wei
Genomic instability induced by DNA damage and improper DNA damage repair is one of the main causes of malignant transformation and tumorigenesis. DNA double strand breaks (DSBs) are the most detrimental form of DNA damage, and nonhomologous end-joining (NHEJ) mechanisms play dominant and priority roles in initiating DSB repair. A well-studied oncogene, the ubiquitin ligase Cullin 4A (CUL4A), is reported to be recruited to DSB sites in genomic DNA, but whether it regulates NHEJ mechanisms of DSB repair is unclear...
February 24, 2021: Oncogene
Yumiao Li, Aiming Zang, Jiejun Fu, Youchao Jia
As a core scaffold protein, Cullin7 (Cul7) forms Skp1-Cullin-F-box (SCF) E3 ubiquitin ligase complexes with the regulator of cullins-1 (ROC1), S-phase kinase associated protein 1 (Skp1) and F-Box, and WD repeat domain containing 8 (Fbxw8). Alternatively, Cul7 can form a CRL7SMU1 complex with suppressor of Mec-8 and Unc-52 protein homolog (SMU1), damage-specific DNA binding protein 1 (DDB1), and ring finger protein 40 (RNF40), to promote cell growth. The mutations of Cul7 cause the 3-M dwarf syndrome, indicating Cul7 plays an important role in growth and development in humans and mice...
February 24, 2021: Neoplasma
Kenneth Wu, Khoi Q Huynh, Iris Lu, Moses Moustakim, Haibin Miao, Clinton Yu, Matthew J Haeusgen, Benjamin D Hopkins, Lan Huang, Ning Zheng, Roberto Sanchez, Robert J DeVita, Zhen-Qiang Pan
Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential...
February 23, 2021: Proceedings of the National Academy of Sciences of the United States of America
Qianqian Song, Siqi Feng, Wenjun Peng, Anqi Li, Ting Ma, Bin Yu, Hong-Min Liu
Gastric carcinoma has serious morbidity and mortality, which seriously threats human health. The studies on gastrointestinal cell biology have shown that the ubiquitination modification that occurs after protein translation plays an essential role in the pathogenesis of gastric carcinoma. Protein ubiquitination is catalyzed by E3 ubiquitin ligase and can regulate various substrate proteins in different cellular pathways. Cullin-RING E3 ligase (CRLs) is a representative of the E3 ubiquitin ligase family, which requires cullin (CUL) neddylation modification for activation to regulate homeostasis of ~20% of cellular proteins...
February 15, 2021: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Miranda J Cullins, John A Russell, Zoe E Booth, Nadine P Connor
Lingual weakness frequently occurs after stroke and is associated with deficits in speaking and swallowing. Chronic weakness after stroke has been attributed to both impaired central activation of target muscles and reduced force generating capacity within muscles. How these factors contribute to lingual weakness is not known. We hypothesized that lingual weakness due to middle cerebral artery occlusion (MCAO) would manifest as reduced muscle force capacity and reduced muscle activation. Rats were randomized into MCAO or sham surgery groups...
February 18, 2021: Journal of Applied Physiology
Guang Lu, Liming Wang, Jing Zhou, Wei Liu, Han-Ming Shen
Autophagy and the ubiquitin-proteasome system (UPS) are two major pathways for protein degradation. The cullin-RING E3 ligases (CRLs) are the largest E3 ligase family and have key biological functions in maintaining protein homeostasis. We provide an updated review of the interactions between CRLs and autophagy, focusing on the regulatory effects of CRLs on the core autophagy machinery that consists of several autophagy-related protein (ATG) complexes and their key upstream signaling pathways. The involvement of such functional interactions in health and disease is also discussed...
February 8, 2021: Trends in Cell Biology
Ai Kaiho-Soma, Yoshino Akizuki, Katsuhide Igarashi, Akinori Endo, Takuji Shoda, Yasuko Kawase, Yosuke Demizu, Mikihiko Naito, Yasushi Saeki, Keiji Tanaka, Fumiaki Ohtake
Targeted protein degradation is an emerging therapeutic paradigm. Small-molecule degraders such as proteolysis-targeting chimeras (PROTACs) induce the degradation of neo-substrates by hijacking E3 ubiquitin ligases. Although ubiquitylation of endogenous substrates has been extensively studied, the mechanism underlying forced degradation of neo-substrates is less well understood. We found that the ubiquitin ligase TRIP12 promotes PROTAC-induced and CRL2VHL -mediated degradation of BRD4 but is dispensable for the degradation of the endogenous CRL2VHL substrate HIF-1α...
February 3, 2021: Molecular Cell
Yang Cao, Hang Zhou, Xiaoyu Chen, Yin Li, Junwen Hu, Guoyang Zhou, Lin Wang
The ubiquitin proteasome system (UPS) serves as the major posttranslational modification system for the maintenance of protein homeostasis. The ubiquitin ligases (E3s) are responsible for the recognition and recruitment of specific substrate proteins for polyubiquitination. Really interesting new gene (RING) finger E3s account for the majority of E3s. The human genome encodes more than 600 RING E3s, which are divided into three subclasses: single polypeptide E3s, cullin-RING ligases (CRLs) and other multisubunit E3s...
February 5, 2021: Biochemical Society Transactions
Daniel Horn-Ghetko, David T Krist, J Rajan Prabu, Kheewoong Baek, Monique P C Mulder, Maren Klügel, Daniel C Scott, Huib Ovaa, Gary Kleiger, Brenda A Schulman
E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates1,2 . However, rather than functioning individually, many neddylated cullin-RING E3 ligases (CRLs) and RBR-type E3 ligases in the ARIH family-which together account for nearly half of all ubiquitin ligases in humans-form E3-E3 super-assemblies3-7 . Here, by studying CRLs in the SKP1-CUL1-F-box (SCF) family, we show how neddylated SCF ligases and ARIH1 (an RBR-type E3 ligase) co-evolved to ubiquitylate diverse substrates presented on various F-box proteins...
February 3, 2021: Nature
Yannan Jiang, Xinyu Liu, Renbin Shen, Xinhua Gu, Weifeng Qian
F-box protein 21 (Fbxo21), a member of the F-box family proteins, constitutes one of the four subunits of an E3 ubiquitin ligase complex called SCFs (SKP1-Cullin-F-box). Despite the effect on antivirus immune response and ubiquitination regulation of a few oncoproteins, such as EID1 and P-gp, little is known about the Fbxo21 function in tumors, including gastric cancer. In our study, we confirmed that Fbxo21 expression was decreased in gastric cancer tissues. Decreased expression of Fbxo21 was significantly associated with poor prognosis in gastric cancer...
2021: Journal of Cancer
Asif A Dar, Keisuke Sawada, Joseph M Dybas, Emily K Moser, Emma L Lewis, Eddie Park, Hossein Fazelinia, Lynn A Spruce, Hua Ding, Steven H Seeholzer, Paula M Oliver
The capacity for T cells to become activated and clonally expand during pathogen invasion is pivotal for protective immunity. Our understanding of how T cell receptor (TCR) signaling prepares cells for this rapid expansion remains limited. Here we provide evidence that the E3 ubiquitin ligase Cullin-4b (Cul4b) regulates this process. The abundance of total and neddylated Cul4b increased following TCR stimulation. Disruption of Cul4b resulted in impaired proliferation and survival of activated T cells. Additionally, Cul4b-deficient CD4+ T cells accumulated DNA damage...
February 1, 2021: PLoS Biology
Ethan Wologo, Sarah Shakil, Scott Zolkos, Sadie Textor, Stephanie Ewing, Jane Klassen, Robert G M Spencer, David C Podgorski, Suzanne E Tank, Michelle A Baker, Jonathan A O'Donnell, Kimberly P Wickland, Sydney S W Foks, Jay P Zarnetske, Joseph Lee-Cullin, Futing Liu, Yuanhe Yang, Pirkko Kortelainen, Jaana Kolehmainen, Joshua F Dean, Jorien E Vonk, Robert M Holmes, Gilles Pinay, Michaela M Powell, Jansen Howe, Rebecca J Frei, Samuel P Bratsman, Benjamin W Abbott
Permafrost degradation is delivering bioavailable dissolved organic matter (DOM) and inorganic nutrients to surface water networks. While these permafrost subsidies represent a small portion of total fluvial DOM and nutrient fluxes, they could influence food webs and net ecosystem carbon balance via priming or nutrient effects that destabilize background DOM. We investigated how addition of biolabile carbon (acetate) and inorganic nutrients (nitrogen and phosphorus) affected DOM decomposition with 28-day incubations...
January 2021: Global Biogeochemical Cycles
Msano Mandalasi, Hyun W Kim, David Thieker, M Osman Sheikh, Elisabet Gas-Pascual, Kazi Rahman, Peng Zhao, Nitin G Daniel, Hanke van der Wel, H Travis Ichikawa, John N Glushka, Lance Wells, Robert J Woods, Zachary A Wood, Christopher M West
Skp1, a subunit of E3 Skp1/Cullin-1/F-box protein ubiquitin ligases, is modified by a prolyl hydroxylase that mediates O2 regulation of the social amoeba Dictyostelium and the parasite Toxoplasma gondii. The full effect of hydroxylation requires modification of the hydroxyproline by a pentasaccharide that, in Dictyostelium, influences Skp1 structure to favor assembly of Skp1/F-box protein subcomplexes. In Toxoplasma, the presence of a contrasting penultimate sugar assembled by a different glycosyltransferase enables testing of the conformational control model...
July 3, 2020: Journal of Biological Chemistry
H-R Liu, J Zhao
OBJECTIVE: To explore the effect and mechanism of miR-217 in cisplatin resistance, as well as invasion and metastasis of ovarian cancer by inhibiting the expression of Cullin 4B (CUL4B) and the activation of Wnt/β-catenin signaling pathway. MATERIALS AND METHODS: Human ovarian cancer cell lines COC1 (cisplatin sensitive) and COC1/DDP (cisplatin resistant) were cultured and were used to construct the COC1 group and COC1/DDP group, respectively. COC1/DDP cells were divided into blank group, NC group, miR-217 mimic group, miR-217 mimic NC group, miR-217 inhibitor group, miR-217 inhibitor NC group, si-CUL4B group, si-CUL4B NC group, overexpressed (oe) oe-CUL4B group, oe-CUL4B NC group, and miR-217 mimic +oe-CUL4B group, with the identification of cell transfection simultaneously...
January 2021: European Review for Medical and Pharmacological Sciences
Hui Wen Lee, Prachi Sharma, Bart J Janssen, Revel S M Drummond, Zhiwei Luo, Cyril Hamiaux, Thomas Collier, Jane R Allison, Richard D Newcomb, Kimberley C Snowden
Strigolactones (SLs) are terpenoid-derived plant hormones that regulate various developmental processes, particularly shoot branching, root development, and leaf senescence. The SL receptor has an unusual mode of action. Upon binding SL, it hydrolyzes the hormone, and then covalently binds one of the hydrolytic products. These initial events enable the SL receptor DAD2 (in petunia) to interact with the F-box protein PhMAX2A of the Skp-Cullin-F-box (SCF) complex and/or a repressor of SL signaling, PhD53A. However, it remains unclear how binding and hydrolysis structurally alters the SL receptor to enable its engagement with signaling partners...
March 27, 2020: Journal of Biological Chemistry
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