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JOURNAL ARTICLE
Muthita Hirunsai, Ratchakrit Srikuea
Renin-angiotensin system activation contributes to skeletal muscle atrophy in aging individuals with chronic diseases. We aimed to explore the effects of cholecalciferol (VD3 ) and calcitriol (1,25VD3 ) on signaling of muscle proteolysis and oxidative stress in myotubes challenged with angiotensin II (AII). The mouse C2C12 myotubes were assigned to vehicle, AII, AII + VD3 , AII + 1,25VD3 , and AII + losartan groups. The expression levels of muscle-specific E3 ubiquitin ligase proteins, autophagy-related proteins, and oxidative stress markers were investigated...
April 2024: Physiological Reports
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JOURNAL ARTICLE
Hirotsugu Oda, Kalpana Manthiram, Pallavi Pimpale Chavan, Eva Rieser, Önay Veli, Öykü Kaya, Charles Rauch, Shuichiro Nakabo, Hye Sun Kuehn, Mariël Swart, Yanli Wang, Nisa Ilgim Çelik, Anne Molitor, Vahid Ziaee, Nasim Movahedi, Mohammad Shahrooei, Nima Parvaneh, Nasrin Alipour-Olyei, Raphael Carapito, Qin Xu, Silvia Preite, David B Beck, Jae Jin Chae, Michele Nehrebecky, Amanda K Ombrello, Patrycja Hoffmann, Tina Romeo, Natalie T Deuitch, Brynja Matthíasardóttir, James Mullikin, Hirsh Komarow, Jennifer Stoddard, Julie Niemela, Kerry Dobbs, Colin L Sweeney, Holly Anderton, Kate E Lawlor, Hiroyuki Yoshitomi, Dan Yang, Manfred Boehm, Jeremy Davis, Pamela Mudd, Davide Randazzo, Wanxia Li Tsai, Massimo Gadina, Mariana J Kaplan, Junya Toguchida, Christian T Mayer, Sergio D Rosenzweig, Luigi D Notarangelo, Kazuhiro Iwai, John Silke, Pamela L Schwartzberg, Bertrand Boisson, Jean-Laurent Casanova, Seiamak Bahram, Anand Prahalad Rao, Nieves Peltzer, Henning Walczak, Najoua Lalaoui, Ivona Aksentijevich, Daniel L Kastner
The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members...
April 12, 2024: Nature Immunology
#3
JOURNAL ARTICLE
Daniel Horn-Ghetko, Linus V M Hopf, Ishita Tripathi-Giesgen, Jiale Du, Sebastian Kostrhon, D Tung Vu, Viola Beier, Barbara Steigenberger, J Rajan Prabu, Luca Stier, Elias M Bruss, Matthias Mann, Yue Xiong, Brenda A Schulman
Ubiquitin ligation is typically executed by hallmark E3 catalytic domains. Two such domains, 'cullin-RING' and 'RBR', are individually found in several hundred human E3 ligases, and collaborate with E2 enzymes to catalyze ubiquitylation. However, the vertebrate-specific CUL9 complex with RBX1 (also called ROC1), of interest due to its tumor suppressive interaction with TP53, uniquely encompasses both cullin-RING and RBR domains. Here, cryo-EM, biochemistry and cellular assays elucidate a 1.8-MDa hexameric human CUL9-RBX1 assembly...
April 11, 2024: Nature Structural & Molecular Biology
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JOURNAL ARTICLE
Jinyuan Xu, Lilin Zhu, Jie Xu, Kailong Lin, Juan Wang, Yan-Long Bi, Guo-Tong Xu, Haibin Tian, Furong Gao, Caixia Jin, Lixia Lu
BACKGROUND: To identify key and shared insulin resistance (IR) molecular signatures across all insulin-sensitive tissues (ISTs), and their potential targeted drugs. METHODS: Three datasets from Gene Expression Omnibus (GEO) were acquired, in which the ISTs (fat, muscle, and liver) were from the same individual with obese mice. Integrated bioinformatics analysis was performed to obtain the differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was carried out to determine the "most significant trait-related genes" (MSTRGs)...
2024: Frontiers in Nutrition
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JOURNAL ARTICLE
D García-Gomis, J López, A Calderón, M Andrés, I Ponte, A Roque
Histone H1 is involved in chromatin compaction and dynamics. In human cells, the H1 complement is formed by different amounts of somatic H1 subtypes, H1.0-H1.5 and H1X. The amount of each variant depends on the cell type, the cell cycle phase, and the time of development and can be altered in disease. However, the mechanisms regulating H1 protein levels have not been described. We have analyzed the contribution of the proteasome to the degradation of H1 subtypes in human cells using two different inhibitors: MG132 and bortezomib...
May 2024: Protein Science
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JOURNAL ARTICLE
Alexander V Skurat, Dyann M Segvich, Christopher J Contreras, Yueh-Chiang Hu, Thomas D Hurley, Anna A DePaoli-Roach, Peter J Roach
Lafora disease (LD) is an autosomal recessive myoclonus epilepsy with onset in the teenage years leading to death within a decade of onset. LD is characterized by the overaccumulation of hyperphosphorylated, poorly branched, insoluble, glycogen-like polymers called Lafora bodies. The disease is caused by mutations in either EPM2A, encoding laforin, a dual specificity phosphatase that dephosphorylates glycogen, or EMP2B, encoding malin, an E3-ubiquitin ligase. While glycogen is a widely accepted laforin substrate, substrates for malin have been difficult to identify partly due to the lack of malin antibodies able to detect malin in vivo...
April 6, 2024: Journal of Biological Chemistry
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JOURNAL ARTICLE
Ehrlichia chaffeensis TRP120 ubiquitinates tumor suppressor APC to modulate Hippo and Wnt signaling.
Caitlan D Byerly, Bing Zhu, Paityn A Warwick, LaNisha L Patterson, Nicholas A Pittner, Jere W McBride
Ehrlichia chaffeensis: TRP120 is a multifunctional effector that acts as a ligand mimic to activate evolutionary conserved eukaryotic signaling pathways Notch, Wnt, Hedgehog and Hippo. In addition, TRP120 is also a HECT E3 ubiquitin ligase known to ubiquitinate several host cell regulatory proteins (FBW7, PCGF5 and ENO-1) for degradation. We previously determined that TRP120 ubiquitinates the Notch negative regulator, FBW7, to maintain Notch signaling and promote infection. In this study, we investigated a potential mechanism used by Ehrlichia chaffeensis to maintain Hippo and Wnt signaling by ubiquitinating the tumor suppressor, adenomatous polyposis coli (APC), a negative regulator of Wnt and Hippo signaling...
2024: Frontiers in Cell and Developmental Biology
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JOURNAL ARTICLE
Junxiong Chen, Yingjun Ding, Chao Jiang, Rongmei Qu, Jonathan D Wren, Constantin Georgescu, Xuejun Wang, Darlene N Reuter, Beibei Liu, Cory B Giles, Christoph H Mayr, Herbert B Schiller, Jingxing Dai, Christopher S Stipp, Bharathiraja Subramaniyan, Jie Wang, Houjuan Zuo, Chao Huang, Kar-Ming Fung, Heather C Rice, Arnoud Sonnenberg, David Wu, Matthew S Walters, You-Yang Zhao, Tomoharu Kanie, Franklin A Hays, James F Papin, Dao Wen Wang, Xin A Zhang
BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation...
April 1, 2024: Circulation Research
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JOURNAL ARTICLE
Sarah F Giardina, Elena Valdambrini, Pradeep K Singh, Manny D Bacolod, Ganesh Babu-Karunakaran, Michael Peel, J David Warren, Francis Barany
Proteolysis-Targeting Chimeras (PROTACs) are bifunctional molecules that bring a target protein and an E3 ubiquitin ligase into proximity to append ubiquitin, thus directing target degradation. Although numerous PROTACs have entered clinical trials, their development remains challenging, and their large size can produce poor drug-like properties. To overcome these limitations, we have modified our Coferon platform to generate Combinatorial Ubiquitination REal-time PROteolysis (CURE-PROs). CURE-PROs are small molecule degraders designed to self-assemble through reversible bio-orthogonal linkers to form covalent heterodimers...
March 30, 2024: Journal of Medicinal Chemistry
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JOURNAL ARTICLE
Dina W Yakout, Ankit Shroff, Wei Wei, Vishrut Thaker, Zachary D Allen, Mathew Sajish, Taras Y Nazarko, Angela M Mabb
Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule-associated protein tau, a main component of neurofibrillary tangles. Alzheimer's disease (AD) is the most common type of tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Besides its role in stabilizing microtubules, tau is localized at postsynaptic sites and can regulate synaptic plasticity. The activity-regulated cytoskeleton-associated protein (Arc), is an immediate early gene that plays a key role in synaptic plasticity, learning and memory...
March 27, 2024: Journal of Biological Chemistry
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JOURNAL ARTICLE
Jamie McElrath Schwartz, Derek K Ng, Jennifer Roem, Nikhil Padmanabhan, Daniel Romero, Jessica Joe, Christopher Campbell, George B Sigal, Jacob N Wohlstadter, Allen D Everett, Melania M Bembea
AIM: We sought to determine if higher plasma levels of brain injury biomarkers neurofilament light (NfL), phosphorylated tau 181 (pT181), tau, and ubiquitin C-terminal hydrolase L1 (UCHL1) were associated with unfavorable outcomes in children supported on extracorporeal membrane oxygenation (ECMO) with and without preceding cardiac arrest. METHODS: We conducted a secondary analysis of a two-center prospective observational study of ECMO patients 0-<18 years...
June 2024: Resuscitation plus
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JOURNAL ARTICLE
J Kent Werner, Jennifer Albrecht, Vincent F Capaldi, Sonia Jain, Xiaoying Sun, Pratik Mukherjee, Scott G Williams, Jacob Collen, Ramon Diaz-Arrastia, Geoffrey T Manley, Andrew D Krystal, Emerson Wickwire
BACKGROUND AND OBJECTIVES: Insomnia affects about one-third of patients with traumatic brain injury and is associated with worsened outcomes after injury. We hypothesized that higher levels of plasma neuroinflammation biomarkers at the time of TBI would be associated with worse 12-month insomnia trajectories. METHODS: Participants were prospectively enrolled from 18 level-1 trauma centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study from February 26, 2014, to August 8, 2018...
April 23, 2024: Neurology
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JOURNAL ARTICLE
Sandi Radko-Juettner, Hong Yue, Jacquelyn A Myers, Raymond D Carter, Alexis N Robertson, Priya Mittal, Zhexin Zhu, Baranda S Hansen, Katherine A Donovan, Moritz Hunkeler, Wojciech Rosikiewicz, Zhiping Wu, Meghan G McReynolds, Shourya S Roy Burman, Anna M Schmoker, Nada Mageed, Scott A Brown, Robert J Mobley, Janet F Partridge, Elizabeth A Stewart, Shondra M Pruett-Miller, Behnam Nabet, Junmin Peng, Nathanael S Gray, Eric S Fischer, Charles W M Roberts
Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3 ...
March 27, 2024: Nature
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JOURNAL ARTICLE
M J M S Kurera, D P Nagahawatta, N M Liyanage, H H A C K Jayawardhana, D S Dissanayake, Hyo-Geun Lee, Young-Sang Kim, Sang In Kang, You-Jin Jeon
Muscle atrophy is a detrimental and injurious condition that leads to reduced skeletal muscle mass and disruption of protein metabolism. Oyster ( Crassostrea nippona ) is a famous and commonly consumed shellfish in East Asia and has become a popular dietary choice worldwide. The current investigation evaluated the efficacy of C. nippona against muscle atrophy, which has become a severe health issue. Mammalian skeletal muscles are primarily responsible for efficient metabolism, energy consumption, and body movements...
February 28, 2024: Marine Drugs
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JOURNAL ARTICLE
Avnika A Ruparelia, Margo Montandon, Jo Merriner, Cheng Huang, Siew Fen Lisa Wong, Carmen Sonntag, Justin P Hardee, Gordon S Lynch, Lee B Miles, Ashley Siegel, Thomas E Hall, Ralf B Schittenhelm, Peter D Currie
Skeletal muscle wasting results from numerous pathological conditions impacting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined...
March 26, 2024: JCI Insight
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JOURNAL ARTICLE
Weiwei Zhang, Yong Liu, Jiajun Zhou, Teng Qiu, Haitang Xie, Zhichen Pu
PURPOSE: This study aimed to examine the impact of CA on DN and elucidate its underlying molecular mechanisms of inflammation. METHODS: We fed C57BL/6 mice injected with streptozotocin to induce diabetes. In addition, we stimulated NRK-52E cells with 20 mmol/L d-glucose to mimic the diabetic condition. RESULTS: Our findings demonstrated that CA effectively reduced blood glucose levels, and improved DN in mice models. Additionally, CA reduced kidney injury and inflammation in both mice models and in vitro models...
December 31, 2024: Clinical and Experimental Hypertension: CHE
#17
JOURNAL ARTICLE
Zhipeng Dong, Beining Yang, Meie Jia, Chang Yang, Shuo Wang, Hailin Mu, Jiawei Wang
Inflammatory environments can trigger endoplasmic reticulum (ER) stress and lead to pyroptosis in various tissues and cells, including liver, brain, and immune cells. As a key factor of ER stress, DNA damage-inducible transcript 3 (DDIT3)/CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is upregulated in osteoblasts during inflammatory stimulation. DDIT3/CHOP may therefore regulate osteoblast pyroptosis in inflammatory conditions. During this investigation, we found that lipopolysaccharides (LPS)/adenosine 5'-triphosphate (ATP) stimulation in vitro induced osteoblasts to undergo pyroptosis, and the expression of DDIT3/CHOP was increased during this process...
March 21, 2024: Biochimica et Biophysica Acta. Molecular Cell Research
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JOURNAL ARTICLE
Hui Liu, Lirong Xu, Enhao Lu, Chenchen Tang, Hanxiao Zhang, Yanwu Xu, Yuanyuan Yu, Naomi Ong, Xiao-Dong Yang, Qilong Chen, Yuejuan Zheng
Influenza virus infection is a worldwide challenge that causes heavy burdens on public health. The mortality rate of severe influenza patients is often associated with hyperactive immunological abnormalities characterized by hypercytokinemia. Due to the continuous mutations and the occurrence of drug-resistant influenza virus strains, the development of host-directed immunoregulatory drugs is urgently required. Platycodon grandiflorum is among the top 10 herbs of traditional Chinese medicine used to treat pulmonary diseases...
March 22, 2024: Journal of Leukocyte Biology
#19
JOURNAL ARTICLE
Zihui Zheng, Miao Chen, Shengliang Feng, Huanhuan Zhao, Tiange Qu, Xudong Zhao, Qinli Ruan, Lei Li, Jun Guo
Close correlation between vitamin D (VitD) deficiency and Parkinson's Disease (PD) risk, VitD as an adjuvant treatment promising to improve PD progression. However, VitD excessive intake could induce hypercalcemia and renal damage. Therefore, upregulation of vitD receptor (VDR) is considered a compensatory strategy to overcome VitD insufficiency and alleviate PD symptoms. In this study, we discovered that VDR played antioxidative roles in dopaminergic neurons by decreasing reactive oxygen species (ROS) and maintaining mitochondrial membrane potential...
March 21, 2024: Cell Death Discovery
#20
JOURNAL ARTICLE
Xiuxiu Lu, Monika Chandravanshi, Venkata R Sabbasani, Snehal Gaikwad, V Keith Hughitt, Nana Gyabaah-Kessie, Bradley T Scroggins, Sudipto Das, Wazo Myint, Michelle E Clapp, Charles D Schwieters, Marzena A Dyba, Derek L Bolhuis, Janusz W Koscielniak, Thorkell Andresson, Michael J Emanuele, Nicholas G Brown, Hiroshi Matsuo, Raj Chari, Deborah E Citrin, Beverly A Mock, Rolf E Swenson, Kylie J Walters
Proteasome subunit hRpn13 is partially proteolyzed in certain cancer cell types to generate hRpn13Pru by degradation of its UCHL5/Uch37-binding DEUBAD domain and retention of an intact proteasome- and ubiquitin-binding Pru domain. By using structure-guided virtual screening, we identify an hRpn13 binder (XL44) and solve its structure ligated to hRpn13 Pru by integrated X-ray crystallography and NMR to reveal its targeting mechanism. Surprisingly, hRpn13Pru is depleted in myeloma cells following treatment with XL44...
March 20, 2024: Nature Communications
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