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signal peptidase

Gemma Pujadas, Daniel J Drucker
Regulatory peptides produced in islet and gut endocrine cells, including glucagon, GLP-1, GLP-2, and GIP exert actions with considerable metabolic importance and translational relevance. Although the clinical development of GLP-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4(DPP4) inhibitors has fostered research into how these hormones act on the normal and diseased heart, less is known about the actions of these peptides on blood vessels. Here we review the effects of these peptide hormones on normal blood vessels, and highlight their vascular actions in the setting of experimental and clinical vascular injury...
October 12, 2016: Endocrine Reviews
Sang Ah Lee, Gwanpyo Koh, Suk Ju Cho, So Yeon Yoo, Sang Ouk Chin
BACKGROUND: Previous studies have reported that glypican-4 (GPC4) regulates insulin signaling by interacting with insulin receptor and through adipocyte differentiation. However, GPC4 has not been studied with regard to its effects on clinical factors in patients with type 2 diabetes mellitus (T2DM). We aimed to identify factors associated with GPC4 level in T2DM. METHODS: Between January 2010 and December 2013, we selected 152 subjects with T2DM and collected serum and plasma into tubes pretreated with aprotinin and dipeptidyl peptidase-4 inhibitor to preserve active gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)...
September 2016: Endocrinology and Metabolism
Brooke A Napier, Sky W Brubaker, Timothy E Sweeney, Patrick Monette, Greggory H Rothmeier, Nina A Gertsvolf, Andreas Puschnik, Jan E Carette, Purvesh Khatri, Denise M Monack
Cell death and release of proinflammatory mediators contribute to mortality during sepsis. Specifically, caspase-11-dependent cell death contributes to pathology and decreases in survival time in sepsis models. Priming of the host cell, through TLR4 and interferon receptors, induces caspase-11 expression, and cytosolic LPS directly stimulates caspase-11 activation, promoting the release of proinflammatory cytokines through pyroptosis and caspase-1 activation. Using a CRISPR-Cas9-mediated genome-wide screen, we identified novel mediators of caspase-11-dependent cell death...
October 3, 2016: Journal of Experimental Medicine
Renzhi Wang, Yakun Yang, Miaomiao Sheng, Dechao Bu, Fengming Huang, Xiaohai Liu, Cuiqi Zhou, Congxin Dai, Bowen Sun, Jindong Zhu, Yi Qiao, Yong Yao, Huijuan Zhu, Lin Lu, Hui Pan, Ming Feng, Kan Deng, Bing Xing, Wei Lian, Yi Zhao, Chengyu Jiang
Adrenocorticotrophin (ACTH)-secreting pituitary adenoma, also known as Cushing disease (CD), is rare and causes metabolic syndrome, cardiovascular disease and osteoporosis due to hypercortisolism. However, the molecular pathogenesis of CD is still unclear because of a lack of human cell lines and animal models. Here, we study 106 clinical characteristics and gene expression changes from 118 patients, the largest cohort of CD in a single-center. RNA deep sequencing is used to examine genotypic changes in nine paired female ACTH-secreting pituitary adenomas and adjacent nontumorous pituitary tissues (ANPT)...
September 29, 2016: International Journal of Molecular Sciences
Shilah A Bonnett, Juliane Ollinger, Susantha Chandrasekera, Stephanie Florio, Theresa O'Malley, Megan Files, Jo-Ann Jee, James Ahn, Allen Casey, Yulia Ovechkina, David Roberts, Aaron Korkegian, Tanya Parish
The general secretion (Sec) pathway is a conserved essential pathway in bacteria and is the primary route of protein export across the cytoplasmic membrane. During protein export, the signal peptidase LepB catalyzes the cleavage of the signal peptide and subsequent release of mature proteins into the extracellular space. We developed a target-based whole cell assay to screen for potential inhibitors of LepB, the sole signal peptidase in Mycobacterium tuberculosis, using a strain engineered to underexpress LepB (LepB-UE)...
September 19, 2016: ACS Infectious Diseases
A Talamillo, L Grande, P Ruiz-Ontañon, C Velasquez, P Mollinedo, S Torices, P Sanchez-Gomez, A Aznar, A Esparis-Ogando, C Lopez-Lopez, C Lafita, M T Berciano, J A Montero, A Vazquez-Barquero, V Segura, N T Villagra, A Pandiella, M Lafarga, J Leon, J A Martinez-Climent, V Sanz-Moreno, J L Fernandez-Luna
Long-term survival remains low for most patients with glioblastoma (GBM), which reveals the need for markers of disease outcome and novel therapeutic targets. We describe that ODZ1 (also known as TENM1), a type II transmembrane protein involved in fetal brain development, plays a crucial role in the invasion of GBM cells. Differentiation of glioblastoma stem-like cells drives the nuclear translocation of an intracellular fragment of ODZ1 through proteolytic cleavage by signal peptide peptidase-like 2a. The intracellular fragment of ODZ1 promotes cytoskeletal remodelling of GBM cells and invasion of the surrounding environment both in vitro and in vivo...
September 19, 2016: Oncogene
Lei Yi, Yan Cui, Qingfu Xu, Yugang Jiang
The substrates and mechanisms of ubiquitin specific peptidase 7 (USP7) in glioma remain unclear. Lysine‑specific demethylase 1 (LSD1) may undergo proteasomal degradation; however, a reciprocal mechanism that stabilizes LSD1 in glioma has not been dertermined. Here co-immunoprecipitation and GST pull-down assays revealed that LSD1 is associated with USP7 in vivo and in vitro. USP7 inhibited LSD1 ubiquitination and stabilized LSD1 in A172 and T98G cells. MTT, EdU proliferation, flow cytometry and Transwell assays indicated that LSD1 played a critical role in the proliferation and invasion of glioblastoma (GBM) cells...
September 16, 2016: Oncology Reports
J Hiroshi Morisaki, Peter A Smith, Shailesh V Date, Kimberly K Kajihara, Chau Linda Truong, Zora Modrusan, Donghong Yan, Jing Kang, Min Xu, Ishita M Shah, Robert Mintzer, Eric M Kofoed, Tommy K Cheung, David Arnott, Michael F T Koehler, Christopher E Heise, Eric J Brown, Man-Wah Tan, Wouter L W Hazenbos
UNLABELLED: The type I signal peptidase of Staphylococcus aureus, SpsB, is an attractive antibacterial target because it is essential for viability and extracellularly accessible. We synthesized compound 103, a novel arylomycin-derived inhibitor of SpsB with significant potency against various clinical S. aureus strains (MIC of ~1 µg/ml). The predominant clinical strain USA300 developed spontaneous resistance to compound 103 with high frequency, resulting from single point mutations inside or immediately upstream of cro/cI, a homolog of the lambda phage transcriptional repressor cro These cro/cI mutations led to marked (>50-fold) overexpression of three genes encoding a putative ABC transporter...
2016: MBio
Ting Wei, Joan Chisholm, Hélène Sanfaçon
The NTB-VPg polyprotein from tomato ringspot virus is an integral membrane replication protein associated with endoplasmic reticulum membranes. A signal peptidase (SPase) cleavage was previously detected in the C-terminal region of NTB-VPg downstream of a 14 amino acid (aa)-long hydrophobic region (termed TM2). However, the exact location of the cleavage site was not determined. Using in vitro translation assays, we show that the SPase cleavage site is conserved in the NTB-VPg protein from various ToRSV isolates, although the rate of cleavage varies from one isolate to another...
2016: PloS One
Fang-Fang Jian, Yun-Feng Li, Yu-Fan Chen, Hong Jiang, Xiao Chen, Li-Li Zheng, Yao Zhao, Wei-Qing Wang, Guang Ning, Liu-Guan Bian, Qing-Fang Sun
BACKGROUND: Two recent whole-exome sequencing researches identifying somatic mutations in the ubiquitin-specific protease 8 (USP8) gene in pituitary corticotroph adenomas provide exciting advances in this field. These mutations drive increased epidermal growth factor receptor (EGFR) signaling and promote adrenocorticotropic hormone (ACTH) production. This study was to investigate whether the inhibition of USP8 activity could be a strategy for the treatment of Cushing's disease (CD). METHODS: The anticancer effect of USP8 inhibitor was determined by testing cell viability, colony formation, apoptosis, and ACTH secretion...
2016: Chinese Medical Journal
Alvaro Banderas, Mihaly Koltai, Alexander Anders, Victor Sourjik
Animals are known to adjust their sexual behaviour depending on mate competition. Here we report similar regulation for mating behaviour in a sexual unicellular eukaryote, the budding yeast Saccharomyces cerevisiae. We demonstrate that pheromone-based communication between the two mating types, coupled to input attenuation by recipient cells, enables yeast to robustly monitor relative mate abundance (sex ratio) within a mixed population and to adjust their commitment to sexual reproduction in proportion to their estimated chances of successful mating...
2016: Nature Communications
Lorenzo Glorie, Patrick C D'Haese, Anja Verhulst
Dipeptidyl peptidase 4 (DPP4) is a conserved exopeptidase with an important function in protein regulation. The activity of DPP4, an enzyme which can either be anchored to the plasma membrane or circulate free in the extracellular compartment, affects the glucose metabolism, cellular signaling, migration and differentiation, oxidative stress and the immune system. DPP4 is also expressed on the surface of osteoblasts, osteoclasts and osteocytes, and was found to play a role in collagen metabolism. Many substrates of DPP4 have an established role in bone metabolism, among which are incretins, gastrointestinal peptides and neuropeptides...
November 2016: Bone
Max M Apolinar-Hernández, Yuri J Peña-Ramírez, Ernesto Pérez-Rueda, Blondy B Canto-Canché, César De Los Santos-Briones, Aileen O'Connor-Sánchez
Metagenomics is a culture-independent technology that allows access to novel and potentially useful genetic resources from a wide range of unknown microorganisms. In this study, a fosmid metagenomic library of tropical underground water was constructed, and clones were functionally screened for extracellular proteolytic activity. One of the positive clones, containing a 41,614-bp insert, had two genes with 60% and 68% identity respectively with a peptidase S8 of Chitinimonas koreensis. When these genes were individually sub-cloned, in both cases their sub-clones showed proteolytic phenotype, confirming that they both encode functional proteases...
November 15, 2016: Gene
Xian-Wei Wang, Fen-Xi Zhang, Fen Yang, Zu-Feng Ding, Nidhi Agarwal, Zhi-Kun Guo, Jawahar L Mehta
AIM: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors can not only lower blood glucose levels, but also alleviate cardiac remodeling after myocardial ischemia and hypertension. In the present study, we investigated the effects of a DPP-4 inhibitor (linagliptin) and a GLP-1 activator (liraglutide) on glucose- and angiotensin II (Ang II)-induced collagen formation and cytoskeleton reorganization in cardiac fibroblasts in vitro, and elucidated the related mechanisms...
September 2016: Acta Pharmacologica Sinica
Amy L Schaefer, Yasuhiro Oda, Bruna Goncalves Coutinho, Dale A Pelletier, Justin Weiburg, Vittorio Venturi, E Peter Greenberg, Caroline S Harwood
UNLABELLED: Homologs of the LuxR acyl-homoserine lactone (AHL) quorum-sensing signal receptor are prevalent in Proteobacteria isolated from roots of the Eastern cottonwood tree, Populus deltoides Many of these isolates possess an orphan LuxR homolog, closely related to OryR from the rice pathogen Xanthomonas oryzae OryR does not respond to AHL signals but, instead, responds to an unknown plant compound. We discovered an OryR homolog, PipR, in the cottonwood endophyte Pseudomonas sp. strain GM79...
2016: MBio
Nikeisha J Caruana, Ira R Cooke, Pierre Faou, Julian Finn, Nathan E Hall, Mark Norman, Sandy S Pineda, Jan M Strugnell
UNLABELLED: Sepiadarium austrinum, the southern bottletail squid, is a small squid that inhabits soft sediments along Australia's south-east coast. When provoked, it rapidly secretes large volumes of slime, presumably as a form of chemical defense. We analyzed the proteomic composition of this slime using tandem mass spectrometry and transcriptomics and found that it was remarkably complex with 1735 identified protein groups (FDR:0.01). To investigate the chemical defense hypothesis we performed an Artemia toxicity assay and used sequence analysis to search for toxin-like molecules...
October 4, 2016: Journal of Proteomics
Satoru Takashima, Hiroki Fujita, Hiromi Fujishima, Tatsunori Shimizu, Takehiro Sato, Tsukasa Morii, Katsushi Tsukiyama, Takuma Narita, Takamune Takahashi, Daniel J Drucker, Yutaka Seino, Yuichiro Yamada
The role of stromal cell-derived factor-1 (SDF-1) in the pathogenesis of diabetic nephropathy and its modification by dipeptidyl peptidase-4 (DPP-4) inhibition are uncertain. Therefore, we studied this independent of glucagon-like peptide-1 receptor (GLP-1R) signaling using two Akita diabetic mouse models, the diabetic-resistant C57BL/6-Akita and diabetic-prone KK/Ta-Akita. Increased SDF-1 expression was found in glomerular podocytes and distal nephrons in the diabetic-prone mice, but not in kidneys from diabetic-resistant mice...
October 2016: Kidney International
Di Wang, Shaowu Li, Jingzhuang Zhao, Hongbai Liu, Tongyan Lu, Jiasheng Yin
Hepcidin, an antimicrobial peptide, plays a crucial role in innate immune system of teleost fish. As a cysteine-rich peptide, hepcidin possesses a dual function including iron regulation and innate immunity. In the present study, a full-length hepcidin cDNA (HtHep) was cloned and characterized by RT-PCR and RACE techniques from taimen (Hucho taimen, Pallas), which is a type of rare, precious and cold-water fish species in China. The cDNA contains an open reading frame (ORF) of 267 bp encoding 88 amino acid (aa), with 170 bp located in the 5(') untranslated region (UTR) and 151 bp in the 3' UTR...
September 2016: Fish & Shellfish Immunology
Shingo Takada, Yoshihiro Masaki, Shintaro Kinugawa, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Masashige Takahashi, Shinichi Harashima, Shouji Matsushima, Takashi Yokota, Shinya Tanaka, Koichi Okita, Hiroyuki Tsutsui
AIMS: Exercise capacity is reduced in heart failure (HF) patients, due mostly to skeletal muscle abnormalities including impaired energy metabolism, mitochondrial dysfunction, fibre type transition, and atrophy. Glucagon-like peptide-1 (GLP-1) has been shown to improve exercise capacity in HF patients. We investigated the effects of the administration of a dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and skeletal muscle abnormalities in an HF mouse model after myocardial infarction (MI)...
September 2016: Cardiovascular Research
Xiaohong Shi, Catherine H Botting, Ping Li, Mark Niglas, Benjamin Brennan, Sally L Shirran, Agnieszka M Szemiel, Richard M Elliott
The M genome segment of Bunyamwera virus (BUNV)-the prototype of both the Bunyaviridae family and the Orthobunyavirus genus-encodes the glycoprotein precursor (GPC) that is proteolytically cleaved to yield two viral structural glycoproteins, Gn and Gc, and a nonstructural protein, NSm. The cleavage mechanism of orthobunyavirus GPCs and the host proteases involved have not been clarified. In this study, we investigated the processing of BUNV GPC and found that both NSm and Gc proteins were cleaved at their own internal signal peptides (SPs), in which NSm domain I functions as SP(NSm) and NSm domain V as SP(Gc) Moreover, the domain I was further processed by a host intramembrane-cleaving protease, signal peptide peptidase, and is required for cell fusion activities...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
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