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Noelle M do Nascimento, Augusto Juste-Dolz, Elena Grau-García, Jose A Román-Ivorra, Rosa Puchades, Angel Maquieira, Sergi Morais, David Gimenez-Romero
An autoantigen piezoelectric sensor to quantify specific circulating autoantibodies in human serum is developed. The sensor consisted on a quartz crystal microbalance with dissipation monitoring (QCM-D) where TRIM21 and TROVE2 autoantigens were covalently immobilized, allowing the selective determination of autoantibodies for diagnosis and prognosis of Systemic Lupus Erythematosus (SLE). The sensitivity of the biosensor, measured as IC50 value, was 1.51U/mL and 0.32U/mL, for anti-TRIM21 and anti-TROVE2 circulating autoantibodies, respectively...
November 9, 2016: Biosensors & Bioelectronics
Maria Bottermann, Heidrun Elisabeth Lode, Ruth E Watkinson, Stian Foss, Inger Sandlie, Jan Terje Andersen, Leo C James
During infection with non-enveloped viruses, antibodies stimulate immunity from inside cells by activating the cytosolic Fc receptor TRIM21. This intracellular humoral response relies on opsonized viral particles reaching the cytosol intact but the antigenic and kinetic constraints involved are unknown. We have solved the structure of a potent TRIM21-dependent neutralizing antibody in complex with human adenovirus 5 hexon and show how these properties influence immune activity. Structure-guided mutagenesis was used to generate antibodies with 20,000-fold variation in affinity, on-rates that differ by ~50-fold and off-rates by >175-fold...
November 24, 2016: Scientific Reports
Jeffrey Q Nguyen, Rosalyn B Irby
The prostate apoptosis response protein 4 (Par-4) is a tumor-suppressor that has been shown to induce cancer-cell selective apoptosis in a variety of cancers. The regulation of Par-4 expression and activity is a relatively understudied area, and identifying novel regulators of Par-4 may serve as novel therapeutic targets. To identify novel regulators of Par-4, a co-immunoprecipitation was performed in colon cancer cells, and co-precipitated proteins were identified by mass-spectometry. TRIM21 was identified as a novel interacting partner of Par-4, and further shown to interact with Par-4 endogenously and through its PRY-SPRY domain...
November 10, 2016: Cancer Biology & Therapy
Marzena Lenart, Magdalena Rutkowska-Zapała, Rafał Szatanek, Kazimierz Węglarczyk, Małgorzata Stec, Karolina Bukowska-Strakova, Anna Gruca, Jarosław Czyż, Maciej Siedlar
Tripartite motif-containing protein 21 (TRIM21) play a dual role in the cytoplasm of the cells where it facilitates destruction of some antibody-coated viruses and some bacteria, and initiates synthesis of proinflammatory cytokines. Macrophages and CD16(+) monocyte subset can particularly participate in a proinflammatory response caused by viral infection, however, the molecular mechanisms underlying these processes are not fully understood. The aim of this study was to determine the level of TRIM21-mRNA expression in monocyte subsets including: classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)) and non-classical (CD14(+)CD16(++)) monocytes, as well as during in vitro differentiation of the isolated monocytes towards dendritic cells or macrophages...
October 18, 2016: Immunobiology
Huai-Peng Lin, Zhou-Li Cheng, Ruo-Yu He, Lei Song, Meng-Xin Tian, Li-Sha Zhou, Beezly S Groh, Wei-Ren Liu, Min-Biao Ji, Chen Ding, Ying-Hong Shi, Kun-Liang Guan, Dan Ye, Yue Xiong
Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacologic inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity, and other diseases. Here, we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin-proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21...
December 1, 2016: Cancer Research
Mariachiara Arisi, Ilaria Cavazzana, Maria E Cerutti, Fabio Ferrari, Nice Carabellese, Maria T Rossi, Angela Tincani, Pier G Calzavara-Pinton, Franco Franceschini
BACKGROUND: Morphea is a rare fibrosing skin disorder. Antinuclear antibodies (ANA), antihistone and rheumatoid factor are detected in high rate of morphea cases. Scleroderma-related antibodies are usually absent. METHODS: 21 adult patients affected by morphea were examined at the time of enrollment and after 6 months with the assessment of clinical outcome measures of disease severity and damage. Healthy subjects were considered as normal controls while patients affected by systemic sclerosis and other connective tissue diseases (CTD) were considered as pathological controls...
October 5, 2016: Giornale Italiano di Dermatologia e Venereologia: Organo Ufficiale, Società Italiana di Dermatologia e Sifilografia
Yan Jiang, Yanping Zhu, Zhi-Jie Liu, Songying Ouyang
RNA helicases are involved in almost every aspect of RNA, from transcription to RNA decay. DExD/H-box helicases comprise the largest SF2 helicase superfamily, which are characterized by two conserved RecA-like domains. In recent years, an increasing number of unexpected functions of these proteins have been discovered. They play important roles not only in innate immune response but also in diseases like cancers and chronic hepatitis C. In this review, we summarize the recent literatures on one member of the SF2 superfamily, the DEAD-box protein DDX41...
August 9, 2016: Protein & Cell
Li Du, Yi-Jia Li, Marwan Fakih, Rebecca L Wiatrek, Marjun Duldulao, Zhenbin Chen, Peiguo Chu, Julio Garcia-Aguilar, Yuan Chen
Cancer stem cells (CSCs) have key roles in treatment resistance, tumour metastasis and relapse. Using colorectal cancer (CC) cell lines, patient-derived xenograft (PDX) tissues and patient tissues, here we report that CC CSCs, which resist chemoradiation, have higher SUMO activating enzyme (E1) and global SUMOylation levels than non-CSCs. Knockdown of SUMO E1 or SUMO conjugating enzyme (E2) inhibits CC CSC maintenance and self-renewal, while overexpression of SUMO E1 or E2 increases CC cell stemness. We found that SUMOylation regulates CSCs through Oct-1, a transcription factor for aldehyde dehydrogenases (ALDHs)...
2016: Nature Communications
Violeta Higuera-Ortiz, Tania Mora-Arias, Diana Castillo-Martinez, Luis M Amezcua-Guerra
OBJECTIVE: To assess whether anti-Ro/SSA antibodies are associated with cardiac valve disease in lupus. METHODS: A single-center, medical chart review was performed. Lupus patients were divided according to its anti-Ro/SSA status and subgroups were compared for valvular abnormalities and other characteristics. Dependence of anti-Ro/SSA reactivity to anti-Ro52/TRIM21 antibodies was also evaluated. RESULTS: Eighty-nine lupus patients were analyzed...
July 18, 2016: Modern Rheumatology
Zhi-Jian Wang, Xiao-Hong Liu, Li Jin, De-Yong Pu, Jing Huang, Yao-Guang Zhang
Rare minnow (Gobiocypris rarus) is a widely used experimental fish in risk assessments of aquatic pollutants in China. Cadmium (Cd) is one of the most toxic heavy metals in the world; however, few studies have used fish gills, a multi-functional organ. In this study, we characterized the differential expression of adult female rare minnow gills after sub-chronic waterborne Cd (75μg/L CdCl2) exposure for 35d. A total of 452 genes (209 up-regulated and 243 down-regulated) were identified by gene expression profiling using RNA-Seq before and after treatment...
September 2016: Comparative Biochemistry and Physiology. Part D, Genomics & Proteomics
Xuejuan Gao, Fengmei Xu, Huan-Tian Zhang, Miaojuan Chen, Wensi Huang, Qihao Zhang, Qingzhong Zeng, Langxia Liu
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a highly promising therapeutic agent for cancer treatment, owing to its ability to selectively target tumor cells for cell death while having little effect on most normal cells. However, recent research has found that many cancers, including non-small cell lung cancer (NSCLC), display resistance to TRAIL. Therefore, it is important to elucidate the molecular mechanisms governing the resistance of tumor cells to TRAIL treatment. In this study, we show that GSK3β antagonized TRAIL-induced apoptosis in H1299 NSCLC cells, and determined that the PKCα isozyme is an upstream regulator of GSK3β that phosphorylates and inactivates GSK3β, thereby sensitizing cancer cells to TRAIL-induced apoptosis...
June 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Ji-An Pan, Yu Sun, Ya-Ping Jiang, Alex J Bott, Nadia Jaber, Zhixun Dou, Bin Yang, Juei-Suei Chen, Joseph M Catanzaro, Chunying Du, Wen-Xing Ding, Maria T Diaz-Meco, Jorge Moscat, Keiko Ozato, Richard Z Lin, Wei-Xing Zong
No abstract text is available yet for this article.
April 7, 2016: Molecular Cell
Andrew J Monteith, SunAh Kang, Eric Scott, Kai Hillman, Zenon Rajfur, Ken Jacobson, M Joseph Costello, Barbara J Vilen
Defects in clearing apoptotic debris disrupt tissue and immunological homeostasis, leading to autoimmune and inflammatory diseases. Herein, we report that macrophages from lupus-prone MRL/lpr mice have impaired lysosomal maturation, resulting in heightened ROS production and attenuated lysosomal acidification. Impaired lysosomal maturation diminishes the ability of lysosomes to degrade apoptotic debris contained within IgG-immune complexes (IgG-ICs) and promotes recycling and the accumulation of nuclear self-antigens at the membrane 72 h after internalization...
April 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
Tomonori Kimura, Ashish Jain, Seong Won Choi, Michael A Mandell, Terje Johansen, Vojo Deretic
Selectivity of autophagy is achieved by target recognition; however, the number of autophagy receptors identified so far is limited. In this study we demonstrate that a subset of tripartite motif (TRIM) proteins mediate selective autophagy of key regulators of inflammatory signaling. MEFV/TRIM20, and TRIM21 act as autophagic receptors recognizing their cognate targets and delivering them for autophagic degradation. MEFV recognizes the inflammasome components NLRP3, CASP1 and NLRP1, whereas TRIM21 recognizes specifically the activated, dimeric from of IRF3 inducing type I interferon gene expression...
March 16, 2016: Autophagy
Stian Foss, Ruth E Watkinson, Algirdas Grevys, Martin B McAdam, Malin Bern, Lene Stokken Høydahl, Bjørn Dalhus, Terje E Michaelsen, Inger Sandlie, Leo C James, Jan Terje Andersen
Ab-coated viruses can be detected in the cytosol by the FcR tripartite motif-containing 21 (TRIM21), which rapidly recruits the proteasomal machinery and triggers induction of immune signaling. As such, TRIM21 plays a key role in intracellular protection by targeting invading viruses for destruction and alerting the immune system. A hallmark of immunity is elicitation of a balanced response that is proportionate to the threat, to avoid unnecessary inflammation. In this article, we show how Ab affinity modulates TRIM21 immune function...
April 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ji-An Pan, Yu Sun, Ya-Ping Jiang, Alex J Bott, Nadia Jaber, Zhixun Dou, Bin Yang, Juei-Suei Chen, Joseph M Catanzaro, Chunying Du, Wen-Xing Ding, Maria T Diaz-Meco, Jorge Moscat, Keiko Ozato, Richard Z Lin, Wei-Xing Zong
TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response...
March 3, 2016: Molecular Cell
Adam J Fletcher, Leo C James
TRIM21 is a high-affinity antibody receptor uniquely expressed in the cytosol of mammalian cells. Here we summarize its role in extending antibody protection into the intracellular environment and allowing nonprofessional cells to benefit from adaptive immunity. We highlight recent work that has shed light on how TRIM21 acts as both an immune sensor and effector. We also review how TRIM21 synergizes with other innate immune receptors to promote an integrated antiviral response.
May 15, 2016: Journal of Virology
Ying Yang, Linyi Peng, Weizhi Ma, Fan Yi, Zhenxi Zhang, Hua Chen, Yongqing Guo, Li Wang, Li Dan Zhao, Wenjie Zheng, Jinghui Li, Fengchun Zhang, Quan Du
MicroRNAs are short endogenous non-coding RNAs that regulate gene expression in various physiological and pathological conditions. To characterize autoantigen-targeting microRNAs in Sjögren's syndrome (SS), a systematic study was carried out, in which a candidate microRNA set was first identified by bioinformatics analysis and literature search. Then, their gene silencing activities were evaluated with fusion reporter gene and endogenous targets, leading to the identification of three microRNAs: TRIM21-targeting miR-1207-5p, TRIM21-targeting miR-4695-3p, and La autoantigen-targeting miR-299-5p...
April 2016: Clinical Rheumatology
Wenchun Fan, Dong Zhang, Ping Qian, Suhong Qian, Mengge Wu, Huanchun Chen, Xiangmin Li
The tripartite motif protein 21 (TRIM21) is a ubiquitously expressed E3 ubiquitin ligase and an intracellular antibody receptor. TRIM21 mediates antibody-dependent intracellular neutralization (ADIN) in cytosol and provides an intracellular immune response to protect host defense against pathogen infection. In this study, swine TRIM21 (sTRIM21) was cloned and its role in ADIN was investigated. The expression of sTRIM21 is induced by type I interferon in PK-15 cells. sTRIM21 restricts FMDV infection in the presence of FMDV specific antibodies...
March 2016: Antiviral Research
Nina Wolska, Paulina Rybakowska, Astrid Rasmussen, Michael Brown, Courtney Montgomery, Arkadiusz Klopocki, Kiely Grundahl, Robert H Scofield, Lida Radfar, Donald U Stone, Juan M Anaya, John A Ice, Christopher J Lessard, David M Lewis, Nelson L Rhodus, Rajaram Gopalakrishnan, Andrew J W Huang, Pamela J Hughes, Michael D Rohrer, Michael H Weisman, Swamy Venuturupalli, Joel M Guthridge, Judith A James, Kathy L Sivils, Harini Bagavant, Umesh S Deshmukh
OBJECTIVE: Autoantibodies reactive with Ro52 (tripartite motif-containing protein 21 [TRIM21]) are detected in 70% of patients with primary Sjögren's syndrome (SS). TRIM21 belongs to a 34-member C-IV family of TRIM proteins. Although autoantibodies against other TRIM proteins within the C-IV family have been detected in the sera of patients with primary SS, their clinical relevance remains unclear. This study was undertaken to investigate the frequency of anti-TRIM38 in patients with primary SS and evaluate its association with various clinical measures of the disease...
March 2016: Arthritis & Rheumatology
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