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https://www.readbyqxmd.com/read/27933060/regulators-of-tfh-cell-differentiation
#1
REVIEW
Gajendra M Jogdand, Suchitra Mohanty, Satish Devadas
The follicular helper T (Tfh) cells help is critical for activation of B cells, antibody class switching, and germinal center (GC) formation. The Tfh cells are characterized by the expression of CXC chemokine receptor 5 (CXCR5), ICOS, programed death 1 (PD-1), B cell lymphoma 6 (BCL-6), and IL-21. They are involved in clearing infections and are adversely linked with autoimmune diseases and also have a role in viral replication as well as clearance. On the one hand, Tfh cells are generated from naive CD4(+) T cells with sequential steps involving cytokine signaling (IL-21, IL-6, IL-12, activin A), migration, and positioning in the GC by CXCR5, surface receptors (ICOS/ICOSL, signaling lymphocyte activation molecule-associated protein/signaling lymphocyte activation molecule) as well as transcription factor (BCL-6, c-Maf, and signal transducer and activator of transcription 3) signaling and repressor miR155...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27932681/acute-intermittent-hypoxia-in-rats-activates-muscle-proteolytic-pathways-through-a-glucocorticoid-dependent-mechanism
#2
Franciele Przygodda, Leandro Henrique Manfredi, Juliano Machado, Dawit A P Gonçalves, Neusa Maria Zanon, Leni G H Bonagamba, Benedito H Machado, Isis do Carmo Kettelhut, Luiz C C Navegantes
Although it is well known that chronic hypoxia induces muscle wasting, the effects of intermit-tent hypoxia on skeletal muscle protein metabolism remains unclear. We hypothesized that acute intermittent hypoxia (AIH), a challenge that activates the hypothalamic-pituitary-adrenal axis, would alter muscle protein homeostasis through a glucocorticoid-dependent mechanism. Three-week-old rats were submitted to adrenalectomy (ADX) and exposed to 8 h of AIH (6% O2 for 40s at 9 min intervals). Animals were sacrificed and the soleus and extensor digitorum longus (EDL) muscles were harvested and incubated in vitro for measurements of protein turn-over...
December 8, 2016: Journal of Applied Physiology
https://www.readbyqxmd.com/read/27932573/fine-tuning-of-ulk1-mrna-and-protein-levels-is-required-for-autophagy-oscillation
#3
Francesca Nazio, Marianna Carinci, Cristina Valacca, Pamela Bielli, Flavie Strappazzon, Manuela Antonioli, Fabiola Ciccosanti, Carlo Rodolfo, Silvia Campello, Gian Maria Fimia, Claudio Sette, Paolo Bonaldo, Francesco Cecconi
Autophagy is an intracellular degradation pathway whose levels are tightly controlled to secure cell homeostasis. Unc-51-like kinase 1 (ULK1) is a conserved serine-threonine kinase that plays a central role in the initiation of autophagy. Here, we report that upon autophagy progression, ULK1 protein levels are specifically down-regulated by the E3 ligase NEDD4L, which ubiquitylates ULK1 for degradation by the proteasome. However, whereas ULK1 protein is degraded, ULK1 mRNA is actively transcribed. Upon reactivation of mTOR-dependent protein synthesis, basal levels of ULK1 are promptly restored, but the activity of newly synthesized ULK1 is inhibited by mTOR...
December 8, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27932568/targeting-hif2-in-clear-cell-renal-cell-carcinoma
#4
Hyejin Cho, William G Kaelin
Inactivation of the von Hippel-Lindau tumor-suppressor protein (pVHL) is the signature "truncal" event in clear cell renal cell carcinoma, which is the most common form of kidney cancer. pVHL is part of a ubiquitin ligase the targets the α subunit of the hypoxia-inducible factor (HIF) transcription factor for destruction when oxygen is available. Preclinical studies strongly suggest that deregulation of HIF, and particularly HIF2, drives pVHL-defective renal carcinogenesis. Although HIF2α was classically considered undruggable, structural and chemical work by Rick Bruick and Kevin Gardner at University of Texas Southwestern laid the foundation for the development of small molecule direct HIF2α antagonists (PT2385 and the related tool compound PT2399) by Peloton Therapeutics that block the dimerization of HIF2α with its partner protein ARNT1...
December 8, 2016: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/27932492/novel-regulatory-roles-of-mff-and-drp1-in-e3-ubiquitin-ligase-march5-dependent-degradation-of-mid49-and-mcl1-and-control-of-mitochondrial-dynamics
#5
Edward Cherok, Shan Xu, Sunan Li, Shweta Das, W Alex Meltzer, Michal Zalzman, Chunxin Wang, Mariusz Karbowski
MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by facilitating release of ubiquitinated proteins from the OMM. We also found that the mitochondrial fission proteins Drp1 and Mff negatively regulate MARCH5's activity toward MiD49 and Mcl1. Knockouts of either Drp1 or Mff led to reduced expression, shorter half-lives, and increased ubiquitination of MiD49 and Mcl1...
December 8, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27932395/ubiquitination-and-the-regulation-of-membrane-proteins
#6
REVIEW
Natalie Foot, Tanya Henshall, Sharad Kumar
Newly synthesized transmembrane proteins undergo a series of steps to ensure that only the required amount of correctly folded protein is localized to the membrane. The regulation of protein quality and its abundance at the membrane are often controlled by ubiquitination, a multistep enzymatic process that results in the attachment of ubiquitin, or chains of ubiquitin to the target protein. Protein ubiquitination acts as a signal for sorting, trafficking, and the removal of membrane proteins via endocytosis, a process through which multiple ubiquitin ligases are known to specifically regulate the functions of a number of ion channels, transporters, and signaling receptors...
January 2017: Physiological Reviews
https://www.readbyqxmd.com/read/27932386/aberrant-expression-of-fbxo2-disrupts-glucose-homeostasis-through-ubiquitin-mediated-degradation-of-insulin-receptor-in-obese-mice
#7
Bin Liu, Han Lu, Duanzhuo Li, Xuelian Xiong, Lu Gao, Zhixiang Wu, Yan Lu
Insulin resistance is a critical factor in the development of metabolic disorders, including type 2 diabetes (T2DM). However, its molecular mechanisms remain incompletely understood. In the present study, we found that F-box only protein 2 (FBXO2), a substrate recognition component of SKP1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase complex, were up-regulated in livers of obese mice. Furthermore, using a protein purification approach combined with high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS), we carried out a system-wide screening of FBXO2 substrates, in which insulin receptor (IR) was identified as a substrate for FBXO2...
December 8, 2016: Diabetes
https://www.readbyqxmd.com/read/27931028/sustained-effects-of-neonatal-systemic-lipopolysaccharide-on-il-1%C3%AE-and-nrf2-in-adult-rat-substantia-nigra-are-partly-normalized-by-a-spirulina-enriched-diet
#8
Jaspal Patil, Ashok Matte, Hans Nissbrandt, Carina Mallard, Mats Sandberg
BACKGROUND/AIM: Neonatal infection can sensitize the adult substantia nigra (SN) to secondary insults, causing a decrease in antioxidant capacity which may lead to Parkinson's disease in adults. We studied the prolonged effect of systemic infection by (i.p.) administration of lipopolysaccharide (LPS) on interleukin (IL)-1β, the antioxidant regulator nuclear factor-erythroid 2-related factor 2 (Nrf2), and the peroxisome proliferator-activated receptor γ coactivator (PGC)-1α in rat SN...
December 9, 2016: Neuroimmunomodulation
https://www.readbyqxmd.com/read/27930322/casitas-b-cell-lymphoma-cbl-proteins-protect-mammary-epithelial-cells-from-proteotoxicity-of-active-c-src-accumulation
#9
Chandrani Mukhopadhyay, Aleata Triplett, Tom Bargar, Carol Heckman, Kay-Uwe Wagner, Mayumi Naramura
Casitas B-cell lymphoma (Cbl) family ubiquitin ligases negatively regulate tyrosine kinase-dependent signal transduction by promoting degradation of active kinases. We and others previously reported that loss of Cbl functions caused hyperproliferation in lymphoid and hematopoietic systems. Unexpectedly, Cbl deletion in Cbl-b-null, Cbl-c-null primary mouse mammary epithelial cells (MECs) (Cbl triple-deficiency) induced rapid cell death despite enhanced MAP kinase and AKT activation. Acute Cbl triple-deficiency elicited distinct transcriptional and biochemical responses with partial overlap with previously described cellular reactions to unfolded proteins and oxidative stress...
December 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27930311/spop-promotes-skeletal-development-and-homeostasis-by-positively-regulating-ihh-signaling
#10
Hongchen Cai, Aimin Liu
Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors. Previous in vitro studies suggested that Speckle-type POZ protein (Spop), part of the Cullin-3 (Cul3) ubiquitin ligase complex, targets Gli2 and Gli3 for degradation and negatively regulates Hedgehog (Hh) signaling. In this study, we found defects in chondrocyte and osteoblast differentiation in Spop-null mutant mice. Strikingly, both the full-length and repressor forms of Gli3, but not Gli2, were up-regulated in Spop mutants, and Ihh target genes Patched 1 (Ptch1) and parathyroid hormone-like peptide (Pthlh) were down-regulated, indicating compromised Hh signaling...
December 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27929533/the-yersinia-type-iii-secretion-effector-yopm-is-an-e3-ubiquitin-ligase-that-induced-necrotic-cell-death-by-targeting-nlrp3
#11
Congwen Wei, Ying Wang, Zongmin Du, Kai Guan, Ye Cao, Huiying Yang, Pengyu Zhou, Feixiang Wu, Jiankang Chen, Penghao Wang, Zirui Zheng, Pingping Zhang, Yanhong Zhang, Shengli Ma, Ruifu Yang, Hui Zhong, Xiang He
Yersinia pestis uses type III effector proteins to target eukaryotic signaling systems. The Yersinia outer protein (Yop) M effector from the Y. pestis strain is a critical virulence determinant; however, its role in Y. pestis pathogenesis is just beginning to emerge. Here we first identify YopM as the structural mimic of the bacterial IpaH E3 ligase family in vitro, and establish that the conserved CLD motif in its N-terminal is responsible for the E3 ligase function. Furthermore, we show that NLRP3 is a novel target of the YopM protein...
December 8, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27929469/the-colon-26-carcinoma-tumor-bearing-mouse-as-a-model-for-the-study-of-cancer-cachexia
#12
Andrea Bonetto, Joseph E Rupert, Rafael Barreto, Teresa A Zimmers
Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality(1). Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma(2-4)...
November 30, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27929429/the-regulation-of-tumor-suppressor-p63-by-the-ubiquitin-proteasome-system
#13
REVIEW
Stephen R Armstrong, Hong Wu, Benfan Wang, Yasser Abuetabh, Consolato Sergi, Roger P Leng
The protein p63 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis, cell cycle arrest, or senescence. p63 has at least six isoforms, which can be divided into two major groups: the TAp63 variants that contain the N-terminal transactivation domain and the ΔNp63 variants that lack the N-terminal transactivation domain. The TAp63 variants are generally considered to be tumor suppressors involved in activating apoptosis and suppressing metastasis. ΔNp63 variants cannot induce apoptosis but can act as dominant negative inhibitors to block the function of TAp53, TAp73, and TAp63...
December 6, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27929086/the-e3-ubiquitin-ligase-trim31-attenuates-nlrp3-inflammasome-activation-by-promoting-proteasomal-degradation-of-nlrp3
#14
Hui Song, Bingyu Liu, Wanwan Huai, Zhongxia Yu, Wenwen Wang, Jing Zhao, Lihui Han, Guosheng Jiang, Lining Zhang, Chengjiang Gao, Wei Zhao
The NLRP3 inflammasome has a fundamental role in host defence against microbial pathogens and its deregulation may cause diverse inflammatory diseases. NLRP3 protein expression is a rate-limiting step for inflammasome activation, thus its expression must be tightly controlled to maintain immune homeostasis and avoid detrimental effects. However, how NLRP3 expression is regulated remains largely unknown. In this study, we identify E3 ubiquitin ligase TRIM31 as a feedback suppressor of NLRP3 inflammasome. TRIM31 directly binds to NLRP3, promotes K48-linked polyubiquitination and proteasomal degradation of NLRP3...
December 8, 2016: Nature Communications
https://www.readbyqxmd.com/read/27927750/mdm2-as-a-chromatin-modifier
#15
REVIEW
Magdalena Wienken, Ute M Moll, Matthias Dobbelstein
Mdm2 is the key negative regulator of the tumour suppressor p53, making it an attractive target for anti-cancer drug design. We recently identified a new role of Mdm2 in gene repression through its direct interaction with several proteins of the polycomb group (PcG) family. PcG proteins form polycomb repressive complexes PRC1 and PRC2. PRC2 (via EZH2) mediates histone 3 lysine 27 (H3K27) trimethylation, and PRC1 (via RING1B) mediates histone 2A lysine 119 (H2AK119) monoubiquitination. Both PRCs mostly support a compact and transcriptionally silent chromatin structure...
November 9, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27927749/modulation-of-the-p53-mdm2-interplay-by-hausp-inhibitors
#16
REVIEW
Omid Tavana, Wei Gu
It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase activity, as well as the protein-protein interaction between p53 and MDM2, is the major focus for this regulation, emerging evidence suggests that the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7) plays a critical role. Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes...
December 6, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27927016/inhibition-of-cathepsin-s-induces-mitochondrial-ros-that-sensitizes-trail-mediated-apoptosis-through-p53-mediated-down-regulation-of-bcl-2-and-c-flip
#17
Bo Ram Seo, Kyoung-Jin Min, Seon Min Woo, Misun Choe, Kyeong Sook Choi, Young-Kyung Lee, Gyesoon Yoon, Taeg Kyu Kwon
AIMS: Cathepsin S is highly expressed in various cancer cells, and it has pro-tumoral effects, including promotion of migration, invasion and neovascularization. In this study, we show that inhibition of cathepsin S could sensitize cancer cells to TRAIL-mediated apoptosis. RESULTS: An inhibitor of cathepsin S (Z-FL-COCHO; ZFL) markedly induced apoptosis in human renal cancer cells treated with TRAIL. In contrast, combined treatment with ZFL and TRAIL had no effect on normal cells...
December 7, 2016: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/27926943/the-mouse-cytomegalovirus-gene-m42-targets-surface-expression-of-the-protein-tyrosine-phosphatase-cd45-in-infected-macrophages
#18
Nadine Thiel, Kirsten A Keyser, Niels A W Lemmermann, Jennifer D Oduro, Karen Wagner, Carina Elsner, Anne Halenius, Tihana Lenac Roviš, Melanie M Brinkmann, Stipan Jonjić, Luka Cicin-Sain, Martin Messerle
The receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is drastically diminished. Screening of a set of MCMV deletion mutants allowed us to identify the viral gene m42 of being responsible for CD45 down-modulation. Moreover, expression of m42 independent of viral infection upon retroviral transduction of the RAW264...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27926878/the-csk-associated-adaptor-pag-inhibits-effector-t-cell-activation-in-cooperation-with-phosphatase-ptpn22-and-dok-adaptors
#19
Dominique Davidson, Ming-Chao Zhong, Pier Paolo Pandolfi, Silvia Bolland, Ramnik J Xavier, Brian Seed, Xin Li, Hua Gu, André Veillette
The transmembrane adaptor PAG (Cbp) has been proposed to mediate membrane recruitment of Csk, a cytoplasmic protein tyrosine kinase playing a critical inhibitory role during T cell activation, by inactivating membrane-associated Src kinases. However, this model has not been validated by genetic evidence. Here, we demonstrate that PAG-deficient mice display enhanced T cell activation responses in effector, but not in naive, T cells. PAG-deficient mice also have augmented T cell-dependent autoimmunity and greater resistance to T cell anergy...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27925369/conventional-and-unconventional-ubiquitination-in-plant-immunity
#20
REVIEW
Bangjun Zhou, Lirong Zeng
Ubiquitination is one of the most abundant types of protein post-translational modifications (PTMs) in plant cells. The importance of ubiquitination in the regulation of many aspects of plant immunity has been increasingly appreciated in recent years. Most of the studies linking ubiquitination to the plant immune system, however, have been focused on the E3 ubiquitin ligases and the conventional ubiquitination that leads to degradation of the substrate proteins by the 26S proteasome. By contrast, our knowledge about the role of unconventional ubiquitination that often plays non-degradative, regulatory role remains a significant gap...
December 7, 2016: Molecular Plant Pathology
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