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Journal of Biological Chemistry

Yung-Chun Wang, Ya-Hui Chuang, Qiang Shao, Jian-Fu Chen, Shi-You Chen
The cardiovascular system develops during the early stages of embryogenesis, and differentiation of smooth muscle cells (SMCs) is essential for that process. SMC differentiation is critically regulated by transforming growth factor (TGF)-β/SMAD family member 3 (SMAD3) signaling, but other regulators may also play a role. For example, long noncoding RNAs (lncRNAs) regulate various cellular activities and events, such as proliferation, differentiation, and apoptosis. However, whether lncRNAs also regulate SMC differentiation remains largely unknown...
February 21, 2018: Journal of Biological Chemistry
Yuqing Shen, John William Sherman, Xuyong Chen, Ruoning Wang
From unicellular to multicellular organisms, cell cycle progression is tightly coupled to biosynthetic and bioenergetic demands. Accumulating evidence has demonstrated the G1/S phase transition as a key checkpoint where cells respond to their metabolic status and commit to replicating the genome. However, the mechanism underlying the coordination of metabolism and the G2/M phase transition in mammalian cells remains unclear. Here we show that the activation of AMP-activated protein kinase (AMPK), a highly conserved cellular energy sensor, significantly delays mitosis entry...
February 21, 2018: Journal of Biological Chemistry
Isai Pratha Karthik, Pavitra Desai, Sudarkodi Sukumar, Aleksandra Dimitrijevic, Krishnaraj Rajalingam, Sundarasamy Mahalingam
Ras proteins are major human oncogenes and most of the studies are focussed on enzymatic RAS effectors. Recently, non-enzymatic Ras effectors (RASSF-Ras association domain family) have garnered special attention because of their tumor suppressive properties in contrast to the oncogenic potential of the classical enzymatic Ras effectors. While most members of RASSF family are deregulated by promoter hypermethylation, RASSF8 promoter remains unmethylated in many cancers but the mechanism(s) of its downregulation remains unknown...
February 21, 2018: Journal of Biological Chemistry
Yanyun Du, Yan Liu, Yujia Xu, Jiaxiang Juan, Zubin Zhang, Zhuan Xu, Biyin Cao, Qi Wang, Yuanying Zeng, Xinliang Mao
Transmembrane prostate androgen-induced protein (TMEPAI, also called prostate transmembrane protein, androgen induced 1 [PMEPA1]), is a type I transmembrane (TM) protein, but its cellular function is largely unknown. Here, studying factors influencing the stability of c-Maf, a critical transcription factor in multiple myeloma (MM), we found that TMEPAI induced c-Maf degradation. We observed that TMEPAI recruited neural precursor cell expressed, developmentally down-regulated 4 (NEDD4), a WW domain-containing ubiquitin ligase, to c-Maf, leading to its degradation through the proteasomal pathway...
February 21, 2018: Journal of Biological Chemistry
George N DeMartino
Autophagy is a highly conserved, tightly regulated cellular process that degrades intracellular constituents via lysosomes. Autophagy mediates many normal cellular functions and is dysregulated in numerous diseases. This Thematic Series consists of five Minireviews that highlight selected topics of current autophagy research ranging from the molecular mechanisms and regulation of autophagy to the roles of autophagy in health and disease.
February 21, 2018: Journal of Biological Chemistry
Perrine Dahan, Vivian Lu, Robert M T Nguyen, Stephanie A L Kennedy, Michael A Teitell
Pluripotent stem cells (PSCs) are highly proliferative cells characterized by robust metabolic demands to power rapid division. For many years considered a passive component or "passenger" of cell fate determination, cell metabolism is now starting to take center stage as a driver of cell fate outcomes. This review provides an update and analysis of our current understanding of PSC metabolism and its role in self-renewal, differentiation, and somatic cell reprogramming to pluripotency. Moreover, we present evidence on the active roles metabolism plays in shaping the epigenome to influence patterns of gene expression that may model key features of early embryonic development...
February 20, 2018: Journal of Biological Chemistry
Fang Huang, Wei Shao, Koh Fujinaga, B Matija Peterlin
Autoimmune regulator (AIRE) and nu-clear factor-kappa B (NF-κB) are transcription factors (TFs) that direct the expression of individual genes and gene clusters. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that recognizes and binds to acetylated histones. BRD4 also has been reported to promote interactions between the positive elongation factor b (P-TEFb) and AIRE or P-TEFb and NF-κB subunit p65. Here, we report that AIRE and p65 bind to P-TEFb independently of BRD4. JQ1, a compound that disrupts interactions between BRD4 and acetylated proteins, does not decrease transcriptional activities of AIRE or p65...
February 20, 2018: Journal of Biological Chemistry
Andrew Huehn, Wenxiang Cao, W Austin Elam, Xueqi Liu, Enrique M De La Cruz, Charles V Sindelar
Cofilin/ADF proteins are actin-remodeling proteins, essential for actin disassembly in various cellular processes, including cell division, intracellular transport, and motility. Cofilins bind actin filaments cooperatively and sever them preferentially at boundaries between bare and cofilin-decorated (cofilactin) segments. The cooperative binding to actin has been proposed to originate from conformational changes that propagate allosterically from clusters of bound cofilin to bare actin segments. Estimates of the lengths over which these cooperative conformational changes propagate vary dramatically, ranging from 2 to >100 subunits...
February 20, 2018: Journal of Biological Chemistry
Thomas Mund, Hugh R Pelham
The Nedd4 family of HECT domain-containing E3 ligases ubiquitinate many transcription factors and signaling proteins, and their activity is tightly regulated. Normally, intramolecular interactions curb the catalytic activity of the HECT domain, but these can be broken by the binding of PY motifs, found on substrate molecules and adaptors, to the WW domains characteristic of this E3 ligase family. This raises the prospect of substrates automatically activating the ligases, frustrating the purpose of ligase regulation...
February 20, 2018: Journal of Biological Chemistry
Julian-Alexander Jentsch, Irene Kiburu, Kalpana Pandey, Michael Timme, Trudy Ramlall, Bodo Levkau, Jin Wu, David Eliezer, Olga Boudker, Anant K Menon
The StARkin superfamily comprises proteins with steroidogenic acute regulatory protein related lipid transfer (StART) domains that are implicated in intracellular, non-vesicular lipid transport. A new family of membrane-anchored StARkins was recently identified, including six members Lam1-Lam6 in the yeast Saccharomyces cerevisiae. Lam1-Lam4 are anchored to the endoplasmic reticulum (ER) membrane at sites where the ER is tethered to the plasma membrane, and proposed to be involved in sterol homeostasis in yeast...
February 20, 2018: Journal of Biological Chemistry
Richard G Carroll, Zbigniew Zaslona, Silvia Galván-Peña, Emma L Koppe, Daniel C Sévin, Stefano Angiari, Martha Triantafilou, Kathy Triantafilou, Louise K Modis, Luke O'Neill
Different immune activation states require distinct metabolic features and activities in immune cells. For instance, inhibition of fatty acid synthase (FASN), which catalyzes the synthesis of long-chain fatty acids, prevents the proinflammatory response in macrophages; however, the precise role of this enzyme in this response remains poorly defined. Consistent with previous studies, we found here that FASN is essential for lipopolysaccharide-induced, Toll-like receptor (TLR)-mediated macrophage activation. Interestingly, only agents that block FASN upstream of acetoacetyl-CoA synthesis, including the well-characterized FASN inhibitor C75, inhibited TLR4 signaling, while those acting downstream had no effect...
February 20, 2018: Journal of Biological Chemistry
Isao Tamura, Kosuke Jozaki, Shun Sato, Yuichiro Shirafuta, Masahiro Shinagawa, Ryo Maekawa, Toshiaki Taketani, Hiromi Asada, Hiroshi Tamura, Norihiro Sugino
We have previously shown that decidualization of human endometrial stromal cells (ESCs) causes a genome-wide increase in the levels of acetylation of histone-H3 Lys-27 (H3K27ac). We also reported that the distal gene regions, more than 3 kb up or downstream of gene transcription start sites have increased H3K27ac levels. Insulin-like growth factor-binding protein-1 (IGFBP-1) is a specific decidualization marker and has increased H3K27ac levels in its distal upstream region (-4701 bp to -7501 bp). Here, using a luciferase reporter gene construct containing this IGFBP-1 upstream region, we tested the hypothesis that it is an IGFBP-1 enhancer...
February 16, 2018: Journal of Biological Chemistry
Alexander Eckersley, Kieran T Mellody, Suzanne M Pilkington, Christopher Em Griffiths, Rachel E B Watson, Ronan O'Cualain, Clair Baldock, David Knight, Michael J Sherratt
Elastic fibres comprising fibrillin microfibrils and elastin are present in many tissues, including the skin, lung, and arteries where they confer elasticity and resilience. Although fibrillin microfibrils play distinct and tissue-specific functional roles, it is unclear whether their ultrastructure and composition differ between elastin-rich (skin) and elastin-poor (ciliary body and zonule) organs or after in vitro synthesis by cultured cells. Here, we used atomic force microscopy, which revealed that the bead morphology of fibrillin microfibrils isolated from the human eye differs from those isolated from the skin...
February 16, 2018: Journal of Biological Chemistry
Timothy J Bergmann, Ilaria Fregno, Fiorenza Fumagalli, Andrea Rinaldi, Francesco Bertoni, Paul J Boersema, Paola Picotti, Maurizio Molinari
The stress sensors ATF6, IRE1 and PERK monitor deviations from homeostatic conditions in the endoplasmic reticulum (ER), a protein biogenesis compartment of eukaryotic cells. Their activation elicits unfolded protein responses (UPR) to re-establish proteostasis. UPR have been extensively investigated in cells exposed to chemicals that activate ER stress sensors by perturbing calcium, N-glycans or redox homeostasis. Cell responses to variations in luminal load with unfolded proteins are, in contrast, poorly characterized...
February 16, 2018: Journal of Biological Chemistry
Denis Susorov, Nikita Zakharov, Ekaterina Shuvalova, Alexander Ivanov, Tatiana Egorova, Alexey Shuvalov, Ivan N Shatsky, Elena Alkalaeva
During protein synthesis, a ribosome moves along the mRNA template and, using aminoacyl-tRNAs, decodes the template nucleotide triplets to assemble a protein amino acid sequence. This movement is accompanied by shifting of mRNA-tRNA complexes within the ribosome in a process called translocation. In living cells, this process proceeds in a unidirectional manner, bringing the ribosome to the 3'-end of mRNA, and is catalyzed by the GTPase translation elongation factor 2 (EF-G in prokaryotes, eEF2 in eukaryotes)...
February 16, 2018: Journal of Biological Chemistry
Chao Qu, Meng Yan, Suming Yang, Lingbo Wang, Qi Yin, Yuan Liu, Yeguang Chen, Jinsong Li
Haploid mammalian embryonic stem cells (haESCs) serve as a powerful tool for genetic analyses at both cellular and organismal levels. However, spontaneous diploidization of haESCs limits their use in these analyses. Addition of small molecules to culture medium to control the cell cycle can slow down diploidization, but cell-sorting methods such as FACS are still required to enrich haploid cells for long-term maintenance in vitro. Here, acting on our observation that haploid and diploidized cells differ in diameter, we developed a simplified filtration method to enrich haploid cells from cultured haESCs...
February 15, 2018: Journal of Biological Chemistry
Diego Esposito, Regina A Günster, Luigi Martino, Kamel El Omari, Armin Wagner, Teresa L M Thurston, Katrin Rittinger
The Salmonella secreted effector SseK3 translocates into host cells, targeting innate immune responses including NF-κB activation. SseK3 is a glycosyltransferase that transfers an N-acetylglucosamine (GlcNAc) moiety onto the guanidino group of a target arginine, modulating host cell function. However, a lack of structural information has precluded elucidation of the molecular mechanisms in arginine and GlcNAc selection. We report here the crystal structure of SseK3 in its apo form and in complex with hydrolysed UDP-GlcNAc...
February 15, 2018: Journal of Biological Chemistry
Wayne S Kontur, Craig A Bingman, Charles N Olmsted, Douglas R Wassarman, Arne Ulbrich, Daniel L Gall, Robert W Smith, Larissa M Yusko, Brian G Fox, Daniel R Noguera, Joshua J Coon, Timothy J Donohue
As a major component of plant cells walls, lignin is a potential renewable source of valuable chemicals. Several sphingomonad bacteria have been identified that can break the β-aryl ether bond connecting most phenylpropanoid units of the lignin heteropolymer. Here, we tested three sphingomonads predicted to be capable of breaking the β-aryl ether bond of the dimeric aromatic compound guaiacylglycerol-β-guaiacyl ether (GGE) and found that Novosphingobium aromaticivorans metabolizes GGE at one of the fastest rates thus far reported...
February 15, 2018: Journal of Biological Chemistry
Inna A Nikonorova, Emily T Mirek, Christina C Signore, Michael P Goudie, Ronald C Wek, Tracy G Anthony
Amino acid availability is sensed by general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1), but how these two sensors coordinate their respective signal transduction events remains mysterious. In this study we utilized mouse genetic models to investigate the role of GCN2 in hepatic mTORC1 regulation upon amino acid stress induced by a single injection of asparaginase. We found that deletion of Gcn2 prevented hepatic phosphorylation of eukaryotic initiation factor 2 alpha (eIF2) to asparaginase and instead unleashed mTORC1 activity...
February 15, 2018: Journal of Biological Chemistry
Dongkai Guo, Shun Zhang, Hongyang Sun, Xingyun Xu, Zongbing Hao, Chenchen Mu, Xingshun Xu, Guanghui Wang, Haigang Ren
Abelson helper integration site 1 (AHI1) is associated with several neuropsychiatric and brain developmental disorders such as schizophrenia, depression, autism, and Joubert syndrome. Ahi1 deficiency in mice leads to behaviors typical of depression. However, the mechanisms by which AHI1 regulates behavior remain to be elucidated. Here, we found that down-regulation of expression of the rate-limiting enzyme in dopamine biosynthesis, tyrosine hydroxylase (TH), in the midbrains of Ahi1 -knockout (KO) mice is responsible for Ahi1 -deficiency-mediated depressive symptoms...
February 15, 2018: Journal of Biological Chemistry
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