scholarly journals Different SUMO Paralogs Determine the Fate of WT and Mutant CFTRs: Biogenesis vs. Degradation

2018 ◽  
Author(s):  
Xiaoyan Gong ◽  
Yong Liao ◽  
Annette Ahner ◽  
Mads Breum Larsen ◽  
Xiaohui Wang ◽  
...  
Keyword(s):  
Physiological Role ◽  
Array Analysis ◽  
Specific Effects ◽  
Ubiquitin Conjugation ◽  
Proteosomal Degradation ◽  
The Common ◽  
Protein Array Analysis ◽  
The Impact

ABSTRACTA pathway for CFTR degradation is initiated by Hsp27 which cooperates with Ubc9 and binds to the common F508del mutant to modify it with SUMO-2/3. These SUMO paralogs form poly-chains, which are recognized by the ubiquitin ligase, RNF4, for proteosomal degradation. Here, protein array analysis identified the SUMO E3, PIAS4, which increased WT and F508del CFTR biogenesis in CFBE airway cells. PIAS4 increased immature CFTR three-fold and doubled expression of mature CFTR, detected by biochemical and functional assays. In cycloheximide chase assays, PIAS4 slowed immature F508del degradation 3-fold and stabilized mature WT CFTR at the PM. PIAS4 knockdown reduced WT and F508del CFTR expression by 40-50%, suggesting a physiological role in CFTR biogenesis. PIAS4 modified F508del CFTR with SUMO-1in vivoand reduced its conjugation to SUMO-2/3. These SUMO paralog specific effects of PIAS4 were reproducedin vitrousing purified F508del NBD1 and SUMOylation reaction components. PIAS4 reduced endogenous ubiquitin conjugation to F508del CFTR by ~50%, and blocked the impact of RNF4 on mutant CFTR disposal. These findings indicate that different SUMO paralogs determine the fates of WT and mutant CFTRs, and they suggest that a paralog switch during biogenesis can direct these proteins to different outcomes: biogenesis vs. degradation.

scholarly journals Different SUMO paralogues determine the fate of wild-type and mutant CFTRs: biogenesis versus degradation

2019 ◽  
Vol 30 (1) ◽  
pp. 4-16 ◽  
Author(s):  
Xiaoyan Gong ◽  
Yong Liao ◽  
Annette Ahner ◽  
Mads Breum Larsen ◽  
Xiaohui Wang ◽  
...  
Keyword(s):  
Physiological Role ◽  
Transmembrane Conductance Regulator ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Specific Effects ◽  
Ubiquitin Conjugation ◽  
Protein Array Analysis ◽  
The Impact

A pathway for cystic fibrosis transmembrane conductance regulator (CFTR) degradation is initiated by Hsp27, which cooperates with Ubc9 and binds to the common F508del mutant to modify it with SUMO-2/3. These SUMO paralogues form polychains, which are recognized by the ubiquitin ligase, RNF4, for proteosomal degradation. Here, protein array analysis identified the SUMO E3, protein inhibitor of activated STAT 4 (PIAS4), which increased wild-type (WT) and F508del CFTR biogenesis in CFBE airway cells. PIAS4 increased immature CFTR threefold and doubled expression of mature CFTR, detected by biochemical and functional assays. In cycloheximide chase assays, PIAS4 slowed immature F508del degradation threefold and stabilized mature WT CFTR at the plasma membrance. PIAS4 knockdown reduced WT and F508del CFTR expression by 40–50%, suggesting a physiological role in CFTR biogenesis. PIAS4 modified F508del CFTR with SUMO-1 in vivo and reduced its conjugation to SUMO-2/3. These SUMO paralogue-specific effects of PIAS4 were reproduced in vitro using purified F508del nucleotide-binding domain 1 and SUMOylation reaction components. PIAS4 reduced endogenous ubiquitin conjugation to F508del CFTR by ∼50% and blocked the impact of RNF4 on mutant CFTR disposal. These findings indicate that different SUMO paralogues determine the fates of WT and mutant CFTRs, and they suggest that a paralogue switch during biogenesis can direct these proteins to different outcomes: biogenesis versus degradation.

scholarly journals Characterization of genetically modified mice for phosphoglycerate mutase, a vitally-essential enzyme in glycolysis

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250856
Author(s):  
Takumi Mikawa ◽  
Eri Shibata ◽  
Midori Shimada ◽  
Ken Ito ◽  
Tomiko Ito ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Knockout Mice ◽  
Physiological Role ◽  
Phosphoglycerate Mutase ◽  
Physiological Homeostasis ◽  
Essential Enzyme ◽  
The Impact

Glycolytic metabolism is closely involved in physiological homeostasis and pathophysiological states. Among glycolytic enzymes, phosphoglycerate mutase (PGAM) has been reported to exert certain physiological role in vitro, whereas its impact on glucose metabolism in vivo remains unclear. Here, we report the characterization of Pgam1 knockout mice. We observed that homozygous knockout mice of Pgam1 were embryonic lethal. Although we previously reported that both PGAM-1 and -2 affect global glycolytic profile of cancers in vitro, in vivo glucose parameters were less affected both in the heterozygous knockout of Pgam1 and in Pgam2 transgenic mice. Thus, the impact of PGAM on in vivo glucose metabolism is rather complex than expected before.

scholarly journals Could β-Lactam Antibiotics Block Humoral Immunity?

2021 ◽  
Vol 12 ◽  
Author(s):  
Cléa Melenotte ◽  
Pierre Pontarotti ◽  
Lucile Pinault ◽  
Jean-Louis Mège ◽  
Christian Devaux ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Opportunistic Infections ◽  
Severe Combined Immunodeficiency ◽  
Physiological Role ◽  
Zinc Ion ◽  
Variable Regions ◽  
The Impact

It has been reported that treatment with β-lactam antibiotics induces leukopenia and candidemia, worsens the clinical response to anticancer immunotherapy and decreases immune response to vaccination. β-lactamases can cleave β-lactam antibiotics by blocking their activity. Two distincts superfamilies of β-lactamases are described, the serine β-lactamases and the zinc ion dependent metallo-β-lactamases. In human, 18 metallo-β-lactamases encoding genes (hMBLs) have been identified. While the physiological role of most of them remains unknown, it is well established that the SNM1A, B and C proteins are involved in DNA repair. The SNM1C/Artemis protein is precisely associated in the V(D)J segments rearrangement, that leads to immunoglobulin (Ig) and T-cell receptor variable regions, which have a crucial role in the immune response. Thus in humans, SNM1C/Artemis mutation is associated with severe combined immunodeficiency characterized by hypogammaglobulinemia deficient cellular immunity and opportunistic infections. While catalytic site of hMBLs and especially that of the SNM1 family is highly conserved, in vitro studies showed that some β-lactam antibiotics, and precisely third generation of cephalosporin and ampicillin, inhibit the metallo-β-lactamase proteins SNM1A & B and the SNM1C/Artemis protein complex. By analogy, the question arises as to whether β-lactam antibiotics can block the SNM1C/Artemis protein in humans inducing transient immunodeficiency. We reviewed here the literature data supporting this hypothesis based on in silico, in vitro and in vivo evidences. Understanding the impact of β-lactam antibiotics on the immune cell will offer new therapeutic clues and new clinical approaches in oncology, immunology, and infectious diseases.

scholarly journals Modulation of Staphylococcus aureus Response to Antimicrobials by the Candida albicans Quorum Sensing Molecule Farnesol

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Eric F. Kong ◽  
Christina Tsui ◽  
Sona Kucharíková ◽  
Patrick Van Dijck ◽  
Mary Ann Jabra-Rizk
Keyword(s):  
Staphylococcus Aureus ◽  
Candida Albicans ◽  
Quorum Sensing ◽  
Physiological Role ◽  
Efflux Pumps ◽  
Content Type ◽  
The Impact ◽  
Quorum Sensing Molecule

ABSTRACT In microbial biofilms, microorganisms utilize secreted signaling chemical molecules to coordinate their collective behavior. Farnesol is a quorum sensing molecule secreted by the fungal species Candida albicans and shown to play a central physiological role during fungal biofilm growth. Our pervious in vitro and in vivo studies characterized an intricate interaction between C. albicans and the bacterial pathogen Staphylococcus aureus, as these species coexist in biofilm. In this study, we aimed to investigate the impact of farnesol on S. aureus survival, biofilm formation, and response to antimicrobials. The results demonstrated that in the presence of exogenously supplemented farnesol or farnesol secreted by C. albicans in biofilm, S. aureus exhibited significantly enhanced tolerance to antimicrobials. By using gene expression studies, S. aureus mutant strains, and chemical inhibitors, the mechanism for the enhanced tolerance was attributed to upregulation of drug efflux pumps. Importantly, we showed that sequential exposure of S. aureus to farnesol generated a phenotype of high resistance to antimicrobials. Based on the presence of intracellular reactive oxygen species upon farnesol exposure, we hypothesize that antimicrobial tolerance in S. aureus may be mediated by farnesol-induced oxidative stress triggering the upregulation of efflux pumps, as part of a general stress response system. Hence, in mixed biofilms, C. albicans may influence the pathogenicity of S. aureus through acquisition of a drug-tolerant phenotype, with important therapeutic implications. Understanding interspecies signaling in polymicrobial biofilms and the specific drug resistance responses to secreted molecules may lead to the identification of novel targets for drug development.

The specification of sympathetic neurotransmitter phenotype depends on gp130 cytokine receptor signaling

Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4791-4801
Author(s):  
M. Geissen ◽  
S. Heller ◽  
D. Pennica ◽  
U. Ernsberger ◽  
H. Rohrer
Keyword(s):  
Sympathetic Neurons ◽  
Physiological Role ◽  
Cholinergic Neurons ◽  
Retroviral Vectors ◽  
Sympathetic Ganglia ◽  
The Common ◽  
Common Signal

Sympathetic ganglia are composed of noradrenergic and cholinergic neurons. The differentiation of cholinergic sympathetic neurons is characterized by the expression of choline acetyltransferase (ChAT) and vasoactive intestinal peptide (VIP), induced in vitro by a subfamily of cytokines, including LIF, CNTF, GPA, OSM and cardiotrophin-1 (CT-1). To interfere with the function of these neuropoietic cytokines in vivo, antisense RNA for gp130, the common signal-transducing receptor subunit for neuropoietic cytokines, was expressed in chick sympathetic neurons, using retroviral vectors. A strong reduction in the number of VIP-expressing cells, but not of cells expressing ChAT or the adrenergic marker tyrosine hydroxylase (TH), was observed. These results reveal a physiological role of neuropoietic cytokines for the control of VIP expression during the development of cholinergic sympathetic neurons.

scholarly journals Zinc Supplementation Modulates NETs Release and Neutrophils’ Degranulation

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 51
Author(s):  
Weronika Kuźmicka ◽  
Aneta Manda-Handzlik ◽  
Adrianna Cieloch ◽  
Agnieszka Mroczek ◽  
Urszula Demkow ◽  
...  
Keyword(s):  
Zinc Supplementation ◽  
Physiological Role ◽  
Zinc Level ◽  
Entire Body ◽  
Isolated Cells ◽  
Zinc Levels ◽  
The Impact ◽  
Deficient Mice

Zinc plays an important physiological role in the entire body, especially in the immune system. It is one of the most abundant microelements in our organism and an essential component of enzymes and antibacterial proteins. Zinc levels were reported to be correlated with the intensity of innate immunity responses, especially those triggered by neutrophils. However, as the results are fragmentary, the phenomenon is still not fully understood and requires further research. In this study, we aimed to perform a comprehensive assessment and study the impact of zinc on several basic neutrophils’ functions in various experimental setups. Human and murine neutrophils were preincubated in vitro with zinc, and then phagocytosis, oxidative burst, degranulation and release of neutrophil extracellular traps (NETs) were analyzed. Moreover, a murine model of zinc deficiency and zinc supplementation was introduced in the study and the functions of isolated cells were thoroughly studied. We showed that zinc inhibits NETs release as well as degranulation in both human and murine neutrophils. Our study revealed that zinc decreases NETs release by inhibiting citrullination of histone H3. On the other hand, studies performed in zinc-deficient mice demonstrated that low zinc levels result in increased release of NETs and enhanced neutrophils degranulation. Overall, it was shown that zinc affects neutrophils’ functions in vivo and in vitro. Proper zinc level is necessary to maintain efficient functioning of the innate immune response.

The Application of the Cold Atmospheric Plasma-Activated Solutions in Cancer Treatment

2018 ◽  
Vol 18 (6) ◽  
pp. 769-775 ◽  
Author(s):  
Dayun Yan ◽  
Jonathan H. Sherman ◽  
Michael Keidar
Keyword(s):  
Cancer Treatment ◽  
Atmospheric Plasma ◽  
Current Status ◽  
Cold Atmospheric Plasma ◽  
Anti Cancer ◽  
Long Time ◽  
Key Topics ◽  
The Common

Background: Over the past five years, the cold atmospheric plasma-activated solutions (PAS) have shown their promissing application in cancer treatment. Similar as the common direct cold plasma treatment, PAS shows a selective anti-cancer capacity in vitro and in vivo. However, different from the direct cold atmospheric plasma (CAP) treatment, PAS can be stored for a long time and can be used without dependence on a CAP device. The research on PAS is gradually becoming a hot topic in plasma medicine. Objectives: In this review, we gave a concise but comprehensive summary on key topics about PAS including the development, current status, as well as the main conclusions about the anti-cancer mechanism achieved in past years. The approaches to make strong and stable PAS are also summarized.

The impact of Zataria multiflora Boiss extract on in vitro and in vivo Th1/Th2 cytokine (IFN-γ/IL4) balance

2013 ◽  
Vol 150 (3) ◽  
pp. 1024-1031 ◽  
Author(s):  
Mohammad Hossein Boskabady ◽  
Sakine Shahmohammadi Mehrjardi ◽  
Abadorrahim Rezaee ◽  
Houshang Rafatpanah ◽  
Sediqeh Jalali
Keyword(s):  
Zataria Multiflora ◽  
Th2 Cytokine ◽  
Ifn Γ ◽  
The Impact

scholarly journals Stu2p binds tubulin and undergoes an open-to-closed conformational change

2006 ◽  
Vol 172 (7) ◽  
pp. 1009-1022 ◽  
Author(s):  
Jawdat Al-Bassam ◽  
Mark van Breugel ◽  
Stephen C. Harrison ◽  
Anthony Hyman
Keyword(s):  
Conformational Change ◽  
Conformational Transition ◽  
Budding Yeast ◽  
Microtubule Dynamics ◽  
Open Structure ◽  
Microtubule Associated Proteins ◽  
Associated Proteins ◽  
The Common

Stu2p from budding yeast belongs to the conserved Dis1/XMAP215 family of microtubule-associated proteins (MAPs). The common feature of proteins in this family is the presence of HEAT repeat–containing TOG domains near the NH2 terminus. We have investigated the functions of the two TOG domains of Stu2p in vivo and in vitro. Our data suggest that Stu2p regulates microtubule dynamics through two separate activities. First, Stu2p binds to a single free tubulin heterodimer through its first TOG domain. A large conformational transition in homodimeric Stu2p from an open structure to a closed one accompanies the capture of a single free tubulin heterodimer. Second, Stu2p has the capacity to associate directly with microtubule ends, at least in part, through its second TOG domain. These two properties lead to the stabilization of microtubules in vivo, perhaps by the loading of tubulin dimers at microtubule ends. We suggest that this mechanism of microtubule regulation is a conserved feature of the Dis1/XMAP215 family of MAPs.

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

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