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signal peptidase

Matthias Bochtler, Danuta Mizgalska, Florian Veillard, Magdalena L Nowak, John Houston, Paul Veith, Eric C Reynolds, Jan Potempa
Bacteroidetes feature prominently in the human microbiome, as major colonizers of the gut and clinically relevant pathogens elsewhere. Here, we reveal a new Bacteroidetes specific feature in the otherwise widely conserved Sec/SPI (Sec translocase/signal peptidase I) pathway. In Bacteroidetes , but not the entire FCB group or related phyla, signal peptide cleavage exposes N-terminal glutamine residues in most SPI substrates. Reanalysis of published mass spectrometry data for five Bacteroidetes species shows that the newly exposed glutamines are cyclized to pyroglutamate (also termed 5-oxoproline) residues...
2018: Frontiers in Microbiology
Weinan Guo, Jinyuan Ma, Tianli Pei, Tao Zhao, Sen Guo, Xiuli Yi, Yu Liu, Shiyu Wang, Guannan Zhu, Zhe Jian, Tianwen Gao, Chunying Li, Wenjun Liao, Qiong Shi
Melanoma is the most malignant skin cancer with increasing incidence worldwide. Although innovative therapies such as BRAF inhibitor and immune checkpoint inhibitor have gained remarkable advances, metastatic melanoma remains an incurable disease for its notorious aggressiveness. Therefore, further clarification of the underlying mechanism of melanoma pathogenesis is critical for the improvement of melanoma therapy. Ubiquitination is an important regulatory event for cancer hallmarks and melanoma development, and the deubiquitinating enzymes including ubiquitin-specific peptidase (USP) families are greatly implicated in modulating cancer biology...
March 14, 2018: Journal of Cellular and Molecular Medicine
Chen Zou, Changjing Han, Minjie Zhao, Jingjing Yu, Lin Bai, Yuan Yao, Shuaixin Gao, Hui Cao, Zhi Zheng
Background: Preoperative treatment of anti-vascular endothelial growth factor (VEGF) agents is extensively used in proliferative diabetic retinopathy (PDR), but the molecular mechanism is not fully understood. The objective of this research is to observe change of protein profile induced by ranibizumab (an anti-VEGF agent) in vitreous humor from PDR patients and reveal the effects of anti-VEGF treatment on PDR. Methods: A proteomic method was used to identify differentially expressed proteins in vitreous humor...
2018: Clinical Proteomics
Rattiyaporn Kanlaya, Visith Thongboonkerd
TGF-β1 is a key fibrotic factor mediating epithelial mesenchymal transition (EMT) of epithelial cells through various signaling pathways. However, roles of proteolytic cleavage and endogenous peptide dynamics in TGF-β1-induced EMT remain unknown. We therefore performed quantitative peptidomics of TGF-β1-induced EMT in renal tubular epithelial cells. The acquired mesenchymal characteristics were confirmed, including morphological change (from cobblestone-like to fibroblast-like), decreased epithelial marker (ZO-1), and increased mesenchymal marker (vimentin)...
December 2018: Cell Death Discovery
Sandra Stefanovic-Barrett, Anna S Dickson, Stephen P Burr, James C Williamson, Ian T Lobb, Dick Jh van den Boomen, Paul J Lehner, James A Nathan
Misfolded or damaged proteins are typically targeted for destruction by proteasome-mediated degradation, but the mammalian ubiquitin machinery involved is incompletely understood. Here, using forward genetic screens in human cells, we find that the proteasome-mediated degradation of the soluble misfolded reporter, mCherry-CL1, involves two ER-resident E3 ligases, MARCH6 and TRC8. mCherry-CL1 degradation is routed via the ER membrane and dependent on the hydrophobicity of the substrate, with complete stabilisation only observed in double knockout MARCH6/TRC8 cells...
March 8, 2018: EMBO Reports
Fernanda Marconi Roversi, Sara Teresinha Olalla Saad, João Agostinho Machado-Neto
Understanding the molecular basis and mechanisms involved in neoplastic transformation and progression is important for the development of novel selective target therapeutic strategies. Hepatocyte growth factor (HGF)/c-MET signaling plays an important role in cell proliferation, survival, migration and motility of cancer cells. Serine peptidase inhibitor Kunitz type 2 (SPINT2) binds to and inactivates the HGF activator (HGFA), behaving as an HGFA inhibitor (HAI) and impairing the conversion of pro-HGF into bioactive HGF...
February 26, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Mun Peak Nyon, Lanying Du, Chien-Te Kent Tseng, Christopher A Seid, Jeroen Pollet, Kevin S Naceanceno, Anurodh Agrawal, Abdullah Algaissi, Bi-Hung Peng, Wanbo Tai, Shibo Jiang, Maria Elena Bottazzi, Ulrich Strych, Peter J Hotez
Middle East respiratory syndrome coronavirus (MERS-CoV) has infected at least 2040 patients and caused 712 deaths since its first appearance in 2012, yet neither pathogen-specific therapeutics nor approved vaccines are available. To address this need, we are developing a subunit recombinant protein vaccine comprising residues 377-588 of the MERS-CoV spike protein receptor-binding domain (RBD), which, when formulated with the AddaVax adjuvant, it induces a significant neutralizing antibody response and protection against MERS-CoV challenge in vaccinated animals...
February 26, 2018: Vaccine
Tao Liu, Jing Ning, Bo Wang, Bin Dong, Song Li, Xiangge Tian, Zhenlong Yu, Yulin Peng, Chao Wang, Xinyu Zhao, Xiaokui Huo, Cheng-Peng Sun, Jing-Nan Cui, Lei Feng, Xiaochi Ma
Visualization of endogenous disease-associated enzymes is of great clinical significance, as it could allow earlier clinical diagnosis and timely intervention. Herein, we first synthesized and characterized an enzyme-activatable near-infrared fluorescent probe, GP-DM, for determining the activity of dipeptidyl peptidase IV (DPP IV), which is associated with various pathological processes, especially in diabetes and malignant tumors. GP-DM emitted significant turn-on NIR fluorescent signals simultaneously in response to DPP IV, making it favorable for accurately and dynamically monitoring DPP IV activity in vitro and in vivo...
March 1, 2018: Analytical Chemistry
Keizo Kanasaki
Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine...
February 28, 2018: Clinical Science (1979-)
Shuai Ye, Matthew A Lawlor, Adrian Rivera-Reyes, Shaun Egolf, Susan Chor, Koreana Pak, Gabrielle E Ciotti, Avery C Lee, Gloria Marino, Jennifer Shah, David Niedzwicki, Kristy Weber, Paul M C Park, Md Zahidul Alam, Alison Grazioli, Malay Haldar, Mousheng Xu, Jennifer A Perry, Jun Qi, T S Karin Eisinger-Mathason
To date, no consistent oncogenic driver mutations have been identified in most adult soft tissue sarcomas; these tumors are thus generally insensitive to existing targeted therapies. Here we investigated alternate mechanisms underlying sarcomagenesis to identify potential therapeutic interventions. Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis...
February 28, 2018: Cancer Research
Nao Sakurai, Shunsuke Nishio, Yuka Akiyama, Shinji Miyata, Kenzi Oshima, Daita Nadano, Tsukasa Matsuda
Casein is the major milk protein to nourish infants but, in certain population, it causes cow's milk allergy, indicating the uptake of antigenic casein and their peptides through the intestinal epithelium. Using human intestinal Caco-2 cell monolayers, the apical-to-basal transepithelial transport of casein was investigated. Confocal microscopy using component-specific antibodies showed that αs1-casein antigens became detectable as punctate signals at the apical-side cytoplasm and reached to the cytoplasm at a tight-junction level within a few hours...
February 27, 2018: Journal of Biochemistry
Jing Gao, Jiajia Song, Min Du, Xueying Mao
Obesity-induced adipose inflammation has been demonstrated to be a key cause of insulin resistance. Peptides derived from bovine α-lactalbumin have been shown to inhibit the activities of dipeptidyl peptidase IV (DPP-IV) and angiotensin converting enzyme (ACE), scavenge 2,2'-azinobis [3-ethylbenzothiazoline-6-sulfonate] (ABTS⁺) radical and stimulate glucagon-like peptide-2 secretion. In the present study, the effects of bovine α-lactalbumin hydrolysates (α-LAH) on adipose insulin resistance and inflammation induced by high-fat diet (HFD) were investigated...
February 23, 2018: Nutrients
Diego R Gelsinger, Jocelyne DiRuggiero
Haloarchaea in their natural environment are exposed to hyper-salinity, intense solar radiation, and desiccation, all of which generate high levels of oxidative stress. Previous work has shown that Haloarchaea are an order of magnitude more resistant to oxidative stress than most mesophilic organisms. Despite this resistance, the pathways Haloarchaea use to respond to oxidative stress damage are similar to that of non-resistant organisms suggesting that regulatory processes might be key to their robustness...
February 20, 2018: Journal of Bacteriology
Vitalie Samoil, Maude Dagenais, Vinupriya Ganapathy, Jerry Aldridge, Anastasia Glebov, Armando Jardim, Paula Ribeiro
Exosomes are small vesicles of endocytic origin, which are released into the extracellular environment and mediate a variety of physiological and pathological conditions. Here we show that Schistosoma mansoni releases exosome-like vesicles in vitro. Vesicles were purified from culture medium by sucrose gradient fractionation and fractions containing vesicles verified by western blot analyses and electron microscopy. Proteomic analyses of exosomal contents unveiled 130 schistosome proteins. Among these proteins are common exosomal markers such as heat shock proteins, energy-generating enzymes, cytoskeletal proteins, and others...
February 19, 2018: Scientific Reports
Youming Ding, Xiaoyan Chen, Bin Wang, Bin Yu, Jianhui Ge
b-AP15, a potent and selective inhibitor of the ubiquitin-specific peptidase 14 (USP14), displays in vitro and in vivo antitumor abilities on some types of cancer cells. However, the mechanism underlying its action is not well elucidated. The purposes of the present study are to observe the potential impacts of b-AP15 on cell survival of hepatocellular carcinoma cells and to investigate whether and how this compound inhibits some survival-promoting signaling pathways. We found that b-AP15 significantly decreased cell viability and increased cell apoptosis in a dose-dependent manner in hepatocellular carcinoma cells, along with the perturbation of cell cycle and the decreased expressions of cell cycle-related proteins...
February 15, 2018: European Journal of Pharmacology
Byeong Hyeok Choi, Changyan Chen, Mark Philips, Wei Dai
RAS proteins are GTPases that participate in multiple signal cascades, regulating crucial cellular processes including cell survival, proliferation, differentiation, and autophagy. Mutations or deregulated activities of RAS are frequently the driving force for oncogenic transformation and tumorigenesis. Given the important roles of the small ubiquitin-related modifier (SUMO) pathway in controlling the stability, activity, or subcellular localization of key cellular regulators, we investigated here whether RAS proteins are posttranslationally modified (i...
January 12, 2018: Oncotarget
Sudha Verma, Abhishek Mandal, Md Yousuf Ansari, Ajay Kumar, Kumar Abhishek, Ayan Kumar Ghosh, Ashish Kumar, Vinod Kumar, Sushmita Das, Pradeep Das
Leishmania donovani , the causative agent of Indian visceral leishmaniasis has to face several barriers of the immune system inside the mammalian host for its survival. The complement system is one of the first barriers and consists of a well-balanced network of proteases including S1A family serine proteases (SPs). Inhibitor of serine peptidases (ISPs) is considered as inhibitor of S1A family serine peptidases and is reported to be present in trypanosomes, including Leishmania . In our previous study, we have deciphered the role of ISPs [LdISP1 and L...
2018: Frontiers in Immunology
Felipe Paredes, Kely Sheldon, Bernard Lassègue, Holly C Williams, Elizabeth A Faidley, Gloria A Benavides, Gloria Torres, Fernanda Sanhueza-Olivares, Samantha M Yeligar, Kathy K Griendling, Victor Darley-Usmar, Alejandra San Martin
Although the addition of the prosthetic group lipoate is essential to the activity of critical mitochondrial catabolic enzymes, its regulation is unknown. Here, we show that lipoylation of the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (αKDH) complexes is a dynamically regulated process that is inhibited under hypoxia and in cancer cells to restrain mitochondrial respiration. Mechanistically, we found that the polymerase-δ interacting protein 2 (Poldip2), a nuclear-encoded mitochondrial protein of unknown function, controls the lipoylation of the pyruvate and α-KDH dihydrolipoamide acetyltransferase subunits by a mechanism that involves regulation of the caseinolytic peptidase (Clp)-protease complex and degradation of the lipoate-activating enzyme Ac-CoA synthetase medium-chain family member 1 (ACSM1)...
February 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
Shylesh Bhaskaran, Gavin Pharaoh, Rojina Ranjit, Ashley Murphy, Satoshi Matsuzaki, Binoj C Nair, Brittany Forbes, Suzana Gispert, Georg Auburger, Kenneth M Humphries, Michael Kinter, Timothy M Griffin, Sathyaseelan S Deepa
Caseinolytic peptidase P (ClpP) is a mammalian quality control protease that is proposed to play an important role in the initiation of the mitochondrial unfolded protein response (UPRmt), a retrograde signaling response that helps to maintain mitochondrial protein homeostasis. Mitochondrial dysfunction is associated with the development of metabolic disorders, and to understand the effect of a defective UPRmt on metabolism, ClpP knockout (ClpP-/-) mice were analyzed. ClpP-/- mice fed ad libitum have reduced adiposity and paradoxically improved insulin sensitivity...
February 2, 2018: EMBO Reports
Sonia Sanz Muñoz, Hongyun Li, Kalani Ruberu, Qian Chu, Alan Saghatelian, Lezanne Ooi, Brett Garner
Apolipoprotein-E (apoE) is a glycoprotein highly expressed in the brain, where it appears to play a role in lipid transport, β-amyloid clearance, and neuronal signaling. ApoE proteolytic fragments are also present in the brain, but the enzymes responsible for apoE fragmentation are unknown, and the biological activity of specific apoE fragments remains to be determined. Here we utilised SK-N-SH neuroblastoma cells differentiated into neurons with all-trans retinoic acid (ATRA) to study extracellular apoE proteolysis...
February 2, 2018: Journal of Biological Chemistry
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