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Luting Yang, Liang Jin, Yao Ke, Xueli Fan, Tongmei Zhang, Chen Zhang, Huijie Bian, Gang Wang
Keratin 17 (K17), a marker of keratinocyte hyperproliferation, is a type I intermediate filament which is overexpressed in psoriatic epidermis and plays a critical pathogenic role by stimulating T cells. However, the posttranslational modification of K17, which is reversible and targetable, has not been elucidated. Herein, we reported that K17 could be modified through ubiquitination that controlled its stability and led to the phosphorylation and nuclear translocation of its interactor STAT3, which is a key regulator of cell proliferation in psoriasis...
May 31, 2018: Journal of Investigative Dermatology
Joshua W Wang, Wai Hong Wu, Tsui-Chin Huang, Margaret Wong, Kihyuck Kwak, Keiko Ozato, Chien-Fu Hung, Richard B S Roden
To address how L2-specific antibodies prevent human papillomavirus (HPV) infection of the genital tract we generated neutralizing monoclonal antibodies (MAbs) WW1, a rat IgG2a that binds L2 residues 17-36 (like mouse MAb RG1), and JWW3, a mouse IgG1 derivative of Mab24 specific to L2 residues 58-64. By Western blot, WW1 recognized L2 of 29/34 HPV genotypes tested, compared to only 13/34 for RG1, and 25/34 for JWW3. WW1 IgG and (Fab')2 bound HPV16 pseudovirions similarly, however whole IgG provided better protection against HPV vaginal challenge...
May 9, 2018: Journal of Virology
Binbin Xue, Huiyi Li, Mengmeng Guo, Jingjing Wang, Yan Xu, Xuan Zou, Rilin Deng, Guangdi Li, Haizhen Zhu
Human innate immunity responds to viral infection by activating the production of interferons (IFNs) and proinflammatory cytokines. The mitochondrial adaptor molecule MAVS plays a critical role in innate immune response to viral infection. In this study, we show that TRIM21 interacts with MAVS to positively regulate innate immunity. Under viral infection, TRIM21 is upregulated through the IFN/JAK/STAT signaling pathway. Knockdown of TRIM21 dramatically impairs innate immune response to viral infection. Moreover, TRIM21 interacts with MAVS and catalyzes the K27-linked polyubiquitination of MAVS, thereby promoting the recruitment of TBK1 to MAVS...
May 9, 2018: Journal of Virology
Qing Zhong Zeng, Wan Ting Liu, Jun Lei Lu, Xiao Hui Liu, Yun Fang Zhang, Lang Xia Liu, Xue Juan Gao
OBJECTIVE: Osteosarcoma is the most common type of malignant bone tumor in children and adolescents. The role of E3 ligases in tumorigenesis is currently a focus in tumor research. In the present study, we investigated the role of the E3 ligase tripartite motif 21 (TRIM21) in osteosarcoma cell proliferation. METHODS: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays were used to assess osteosarcoma cell viability. U2-OS cells stably carrying a recombinant lentivirus expressing tetracycline-regulated TRIM21 were screened...
March 2018: Biomedical and Environmental Sciences: BES
Claire Dickson, Adam J Fletcher, Marina Vaysburd, Ji-Chun Yang, Donna L Mallery, Jingwei Zeng, Christopher M Johnson, Stephen H McLaughlin, Mark Skehel, Sarah Maslen, James Cruickshank, Nicolas Huguenin-Dezot, Jason W Chin, David Neuhaus, Leo C James
Cell surface Fc receptors activate inflammation and are tightly controlled to prevent autoimmunity. Antibodies also simulate potent immune signalling from inside the cell via the cytosolic antibody receptor TRIM21, but how this is regulated is unknown. Here we show that TRIM21 signalling is constitutively repressed by its B-Box domain and activated by phosphorylation. The B-Box occupies an E2 binding site on the catalytic RING domain by mimicking E2-E3 interactions, inhibiting TRIM21 ubiquitination and preventing immune activation...
April 18, 2018: ELife
Henry H Nguyen, Abdel Aziz Shaheen, Natalia Baeza, Ellina Lytvyak, Stefan J Urbanski, Andrew L Mason, Gary L Norman, Marvin J Fritzler, Mark G Swain
BACKGROUND AND AIMS: Up to 20% of Primary Biliary Cholangitis (PBC) patients are estimated to have features that overlap with Autoimmune Hepatitis (AIH). Patients with PBC-AIH overlap syndrome (PBC-AIH OS) have been reported to exhibit suboptimal responses to ursodeoxycholic acid therapy, and are more likely to progress to cirrhosis. Anti-double stranded DNA (anti-dsDNA) and anti-p53 have been previously suggested to be potential autoantibodies for identifying patients with PBC-AIH OS...
2018: PloS One
Maria Bottermann, Leo C James
Innate immunity is traditionally thought of as the first line of defense against pathogens that enter the body. It is typically characterized as a rather weak defense mechanism, designed to restrict pathogen replication until the adaptive immune response generates a tailored response and eliminates the infectious agent. However, intensive research in recent years has resulted in better understanding of innate immunity as well as the discovery of many effector proteins, revealing its numerous powerful mechanisms to defend the host...
2018: Advances in Virus Research
Junji Itou, Wenzhao Li, Shinji Ito, Sunao Tanaka, Yoshiaki Matsumoto, Fumiaki Sato, Masakazu Toi
Sal-like 4 (SALL4) is a transcription factor that enhances proliferation and migration in breast cancer cells. SALL4 expression therefore has the potential to promote cancer malignancy. However, the regulatory mechanisms involved in SALL4 protein expression have not been thoroughly elucidated. In this study, we observed that treating MCF-7 and SUM159 breast cancer cell lines with a proteasome inhibitor increases SALL4 protein levels, suggesting that SALL4 is degraded by the ubiquitin-proteasome system. Using immunoprecipitation to uncover SALL4-binding proteins, we identified an E3 ubiquitin-protein ligase, tripartite motif-containing 21 (TRIM21)...
April 27, 2018: Journal of Biological Chemistry
Vesela Encheva, Clémence Foltz, Ambrosius P Snijders, Eva-Maria Frickel
OBJECTIVE: The intracellular parasite Toxoplasma gondii can invade any nucleated cell residing inside a parasitophorous vacuole (PV). Upon infection, the cytokine interferon gamma (IFNγ) is produced and elicits host defence mechanisms able to recognise the PV and destroy the parasite. Hereby, Guanylate binding proteins, ubiquitin and the E3 ubiquitin ligases Tripartite Motif Containing 21 (TRIM21) and TNF receptor associated factor 6 are targeted to the murine PV leading to its destruction...
March 6, 2018: BMC Research Notes
Peter D Burbelo, Leyla Y Teos, Jesse L Herche, Michael J Iadarola, Ilias Alevizos
Ro52/TRIM21 plays a key role in antibody-dependent pathogen neutralization and is a major autoantigen in systemic lupus erythematosus, Sjögren's syndrome (SS), and other autoimmune diseases. Here we evaluated immunoreactivity against Ro52-related molecules in SS and healthy volunteers. Although most proteins examined were not antigenic, several TRIM paralogs, including TRIM22, and TRIM38, showed sporadic immunoreactivity in SS. In contrast, the murine Ro52 ortholog with limited linear homology demonstrated high levels of autoantibodies implicating the importance of shared conformational epitopes...
February 20, 2018: Scientific Reports
Zsofia Agod, Kitti Pazmandi, Dora Bencze, Gyorgy Vereb, Tamas Biro, Attila Szabo, Eva Rajnavolgyi, Attila Bacsi, Pablo Engel, Arpad Lanyi
Signaling lymphocyte activation molecule family (SLAMF) receptors are essential regulators of innate and adaptive immune responses. The function of SLAMF5/CD84, a family member with almost ubiquitous expression within the hematopoietic lineage is poorly defined. In this article, we provide evidence that in human monocyte-derived dendritic cells (moDCs) SLAMF5 increases autophagy, a degradative pathway, which is highly active in dendritic cells (DCs) and plays a critical role in orchestration of the immune response...
2018: Frontiers in Immunology
Reikou Kamiyama, Ryusuke Yoshimi, Mitsuhiro Takeno, Yasuhiro Iribe, Toshinori Tsukahara, Daiga Kishimoto, Yosuke Kunishita, Yumiko Sugiyama, Naomi Tsuchida, Hiroto Nakano, Kaoru Minegishi, Maasa Tamura, Yukiko Asami, Yohei Kirino, Yoshiaki Ishigatsubo, Keiko Ozato, Hideaki Nakajima
OBJECTIVES: TRIM21 is an E3 ubiquitin ligase for interferon regulatory factors (IRFs) that are involved in innate and acquired immunity. Here, we evaluated the role of TRIM21 in the interferon (IFN) signature of systemic lupus erythematosus (SLE). METHODS: Twenty SLE patients and 24 healthy controls were enrolled in this study. We analyzed mRNA expression of TRIM21, type I IFN, and IFN-inducible genes in peripheral blood mononuclear cell (PBMC). The protein levels of IRFs were assessed by Western blotting in PBMCs cultured with or without MG-132...
February 23, 2018: Modern Rheumatology
Jun-Fang Zhang, Hua-Long Xiong, Jia-Li Cao, Shao-Juan Wang, Xue-Ran Guo, Bi-Yun Lin, Ying Zhang, Jing-Hua Zhao, Ying-Bin Wang, Tian-Ying Zhang, Quan Yuan, Jun Zhang, Ning-Shao Xia
Rationale: Monoclonal antibodies (mAbs) mostly targeting extracellular or cell surface molecules have been widely used in the treatment of various diseases. However, mAbs cannot pass through the cell membrane as efficiently as small compounds, thus limiting their use against intracellular targets. Methods to shuttle antibodies into living cells may largely expand research and application in areas based on mAbs. Hepatitis B virus X protein (HBx) is an important intracellular multi-functional viral protein in the life cycle of hepatitis B virus (HBV)...
2018: Theranostics
Kseniya Khamina, Alexander Lercher, Michael Caldera, Christopher Schliehe, Bojan Vilagos, Mehmet Sahin, Lindsay Kosack, Anannya Bhattacharya, Peter Májek, Alexey Stukalov, Roberto Sacco, Leo C James, Daniel D Pinschewer, Keiryn L Bennett, Jörg Menche, Andreas Bergthaler
RNA-dependent RNA polymerases (RdRps) play a key role in the life cycle of RNA viruses and impact their immunobiology. The arenavirus lymphocytic choriomeningitis virus (LCMV) strain Clone 13 provides a benchmark model for studying chronic infection. A major genetic determinant for its ability to persist maps to a single amino acid exchange in the viral L protein, which exhibits RdRp activity, yet its functional consequences remain elusive. To unravel the L protein interactions with the host proteome, we engineered infectious L protein-tagged LCMV virions by reverse genetics...
December 2017: PLoS Pathogens
A Gullà, T Hideshima, G Bianchi, M Fulciniti, M Kemal Samur, J Qi, Y-T Tai, T Harada, E Morelli, N Amodio, R Carrasco, P Tagliaferri, N C Munshi, P Tassone, K C Anderson
Arginine methyltransferases critically regulate cellular homeostasis by modulating the functional outcome of their substrates. The protein arginine methyltransferase 5 (PRMT5) is an enzyme involved in growth and survival pathways promoting tumorigenesis. However, little is known about the biologic function of PRMT5 and its therapeutic potential in multiple myeloma (MM). In the present study, we identified and validated PRMT5 as a new therapeutic target in MM. PRMT5 is overexpressed in patient MM cells and associated with decreased progression-free survival and overall survival...
April 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Guangxi Zhou, Wei Wu, Lin Yu, Tianming Yu, Wenjing Yang, Ping Wang, Xiaoping Zhang, Yingzi Cong, Zhanju Liu
BACKGROUND: Tripartite motif-containing (TRIM) 21 has been implicated in the pathogenesis of several types of autoimmune diseases. OBJECTIVE: We sought to elucidate TRIM21 expression in patients with inflammatory bowel diseases (IBDs) and its role in regulating intestinal mucosal inflammation. METHODS: TRIM21 expression was analyzed in the inflamed mucosa of patients with IBDs by means of quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4+ T cells were transfected with lentivirus-expressing TRIM21 (LV-TRIM21) or LV-sh-TRIM21, and cytokine expression was determined by using quantitative RT-PCR and ELISA...
November 4, 2017: Journal of Allergy and Clinical Immunology
Jong-Ho Lee, Rui Liu, Jing Li, Chuanbao Zhang, Yugang Wang, Qingsong Cai, Xu Qian, Yan Xia, Yanhua Zheng, Yuji Piao, Qianming Chen, John F de Groot, Tao Jiang, Zhimin Lu
Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis; however, its role and regulation in tumorigenesis are not well understood. Here, we demonstrate that PFK1 platelet isoform (PFKP) is the predominant PFK1 isoform in human glioblastoma cells and its expression correlates with total PFK activity. We show that PFKP is overexpressed in human glioblastoma specimens due to an increased stability, which is induced by AKT activation resulting from phosphatase and tensin homologue (PTEN) loss and EGFR-dependent PI3K activation...
October 16, 2017: Nature Communications
Susanna Brauner, Xintong Jiang, Gudny Ella Thorlacius, Anna M Lundberg, Therese Östberg, Zhong-Qun Yan, Vijay K Kuchroo, Göran K Hansson, Marie Wahren-Herlenius
Aims: Patients with hyperlipidemia are at risk of atherosclerosis, but not all develop cardiovascular disease, highlighting the importance of other risk factors such as inflammation. Both the innate and adaptive arms of the immune system have been suggested in the initiation and propagation of plaque formation. Tri-partite motif (TRIM) 21 is a regulator of tissue inflammation and pro-inflammatory cytokine production, and has been implicated in chronic inflammatory disease. Here, we investigate a potential role for TRIM21 in coronary artery disease...
January 1, 2018: Cardiovascular Research
Mohamed Yahya, Maris Rulli, Laura Toivonen, Matti Waris, Ville Peltola
Respiratory viruses frequently cause symptomatic infections in children but are often detected also in healthy children. We investigated myxovirus resistance protein A (MxA), viperin, and tripartite-motif 21 (TRIM21) messenger RNA indexes in nasal swabs as potential biomarkers of viral respiratory infection in children. Respiratory viruses were detected by polymerase chain reaction in the same swabs. Nasal MxA and viperin indexes were increased in symptomatic virus-positive children. Nasal viperin index was found to be a robust marker of viral respiratory tract infection with a sensitivity of 80% and specificity of 94% in distinguishing children with symptomatic virus infections from asymptomatic virus-negative children...
November 27, 2017: Journal of Infectious Diseases
David A Rhodes, David A Isenberg
Therapeutic antibodies targeting disease-associated antigens are key tools in the treatment of cancer and autoimmunity. So far, therapeutic antibodies have targeted antigens that are, or are presumed to be, extracellular. A largely overlooked property of antibodies is their functional activity inside cells. The diverse literature dealing with intracellular antibodies emerged historically from studies of the properties of some autoantibodies. The identification of tripartite motif (TRIM) 21 as an intracellular Fc receptor linking cytosolic antibody recognition to the ubiquitin proteasome system brings this research into sharper focus...
December 2017: Trends in Immunology
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