scholarly journals Unraveling Human AQP5-PIP Molecular Interaction and Effect on AQP5 Salivary Glands Localization in SS Patients

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2108
Author(s):  
Clara Chivasso ◽  
Veronika Nesverova ◽  
Michael Järvå ◽  
Anne Blanchard ◽  
Kristie L Rose ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Apical Membrane ◽  
Water Channel ◽  
Breast Cancers ◽  
Aquaporin 5 ◽  
Saliva Secretion ◽  
C Terminus ◽  
Inducible Protein

Saliva secretion requires effective translocation of aquaporin 5 (AQP5) water channel to the salivary glands (SGs) acinar apical membrane. Patients with Sjögren’s syndrome (SS) display abnormal AQP5 localization within acinar cells from SGs that correlate with sicca manifestation and glands hypofunction. Several proteins such as Prolactin-inducible protein (PIP) may regulate AQP5 trafficking as observed in lacrimal glands from mice. However, the role of the AQP5-PIP complex remains poorly understood. In the present study, we show that PIP interacts with AQP5 in vitro and in mice as well as in human SGs and that PIP misexpression correlates with an altered AQP5 distribution at the acinar apical membrane in PIP knockout mice and SS hMSG. Furthermore, our data show that the protein-protein interaction involves the AQP5 C-terminus and the N-terminal of PIP (one molecule of PIP per AQP5 tetramer). In conclusion, our findings highlight for the first time the role of PIP as a protein controlling AQP5 localization in human salivary glands but extend beyond due to the PIP-AQP5 interaction described in lung and breast cancers.

scholarly journals The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 265 ◽  
Author(s):  
Sathish Murali ◽  
Takwa Aroankins ◽  
Hanne Moeller ◽  
Robert Fenton
Keyword(s):  
Collecting Duct ◽  
Water Channel ◽  
Mouse Kidney ◽  
Body Water ◽  
Mrna Levels ◽  
E3 Ligases ◽  
Water Homeostasis ◽  
And Function

Aquaporin 2 (AQP2) mediates the osmotic water permeability of the kidney collecting duct in response to arginine vasopressin (VP) and is essential for body water homeostasis. VP effects on AQP2 occur via long-term alterations in AQP2 abundance and short-term changes in AQP2 localization. Several of the effects of VP on AQP2 are dependent on AQP2 phosphorylation and ubiquitylation; post-translational modifications (PTM) that modulate AQP2 subcellular distribution and function. Although several protein kinases, phosphatases, and ubiquitin E3 ligases have been implicated in AQP2 PTM, how AQP2 is deubiquitylated or the role of deubiquitylases (DUBS) in AQP2 function is unknown. Here, we report a novel role of the ubiquitin-specific protease USP4 in modulating AQP2 function. USP4 co-localized with AQP2 in the mouse kidney, and in mpkCCD14 cells USP4 and AQP2 abundance are increased by VP. AQP2 and USP4 co-immunoprecipitated from mpkCCD14 cells and mouse kidney, and in vitro, USP4 can deubiquitylate AQP2. In mpkCCD14 cells, shRNA mediated knockdown of USP4 decreased AQP2 protein abundance, whereas no changes in AQP2 mRNA levels or VP-induced cAMP production were detected. VP-induced AQP2 membrane accumulation in knockdown cells was significantly reduced, which was associated with higher levels of ubiquitylated AQP2. AQP2 protein half-life was also significantly reduced in USP4 knockdown cells. Taken together, the data suggest that USP4 is a key regulator of AQP2 deubiquitylation and that loss of USP4 leads to increased AQP2 ubiquitylation, decreased AQP2 levels, and decreased cell surface AQP2 accumulation upon VP treatment. These studies have implications for understanding body water homeostasis.

scholarly journals Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1918
Author(s):  
Yanyuan Wu ◽  
Marianna Sarkissyan ◽  
Ochanya Ogah ◽  
Juri Kim ◽  
Jaydutt V. Vadgama
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Akt Pathway ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Mesenchymal Transition ◽  
Cancer Tissues

Background: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with cancer progression. Our study examined the role of MALAT1 in breast cancer and the mechanisms involved in the regulation of MALAT1. Methods: In vitro cell and in vivo animal models were used to examine the role of MALAT1 in breast cancer. The interaction of FOXO1 (Forkhead Box O1) at the promoter region of MALAT1 was investigated by chromatin immunoprecipitation (ChIP) assay. Results: The data shows an elevated expression of MALAT1 in breast cancer tissues and cells compared to non-cancer tissues and cells. The highest level of MALAT1 was observed in metastatic triple-negative breast cancer and trastuzumab-resistant HER2 (human epidermal growth factor receptor 2) overexpressing (HER2+) cells. Knockdown of MALAT1 in trastuzumab-resistant HER2+ cells reversed epithelial to mesenchymal transition-like phenotype and cell invasiveness. It improved the sensitivity of the cell’s response to trastuzumab. Furthermore, activation of Akt by phosphorylation was associated with the upregulation of MALAT1. The transcription factor FOXO1 regulates the expression of MALAT1 via the PI3/Akt pathway. Conclusions: We show that MALAT1 contributes to HER2+ cell resistance to trastuzumab. Targeting the PI3/Akt pathway and stabilizing FOXO1 translocation could inhibit the upregulation of MALAT1.

scholarly journals Conventional Kinesin Mediates Microtubule-Microtubule Interactions In Vivo

2006 ◽  
Vol 17 (2) ◽  
pp. 907-916 ◽  
Author(s):  
Anne Straube ◽  
Gerd Hause ◽  
Gero Fink ◽  
Gero Steinberg
Keyword(s):  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Binding Activity ◽  
C Terminus ◽  
Cross Bridges ◽  
Conventional Kinesin ◽  
Motor Head

Conventional kinesin is a ubiquitous organelle transporter that moves cargo toward the plus-ends of microtubules. In addition, several in vitro studies indicated a role of conventional kinesin in cross-bridging and sliding microtubules, but in vivo evidence for such a role is missing. In this study, we show that conventional kinesin mediates microtubule-microtubule interactions in the model fungus Ustilago maydis. Live cell imaging and ultrastructural analysis of various mutants in Kin1 revealed that this kinesin-1 motor is required for efficient microtubule bundling and participates in microtubule bending in vivo. High levels of Kin1 led to increased microtubule bending, whereas a rigor-mutation in the motor head suppressed all microtubule motility and promoted strong microtubule bundling, indicating that kinesin can form cross-bridges between microtubules in living cells. This effect required a conserved region in the C terminus of Kin1, which was shown to bind microtubules in vitro. In addition, a fusion protein of yellow fluorescent protein and the Kin1tail localized to microtubule bundles, further supporting the idea that a conserved microtubule binding activity in the tail of conventional kinesins mediates microtubule-microtubule interactions in vivo.

Enzyme-Activities Associated With Salivary-Glands of the Froghopper Eoscarta-Carnifex (F) (Homoptera, Cercopoidae) - Possible Role of Salivary Catalase in Phytotoxicity

1992 ◽  
Vol 40 (4) ◽  
pp. 365 ◽  
Author(s):  
DH Rodman ◽  
DJ Miller
Keyword(s):  
Salivary Glands ◽  
Enzyme Activities ◽  
New World ◽  
Yield Losses ◽  
Injury Response ◽  
Plant Peroxidase ◽  
Major Injury ◽  
Plant Injury

'Froghopper blight', systemic damage caused by an unidentified toxin in the saliva of various homopterans (superfamily Cercopoidea), is responsible for massive yield losses in many sugarcane-growing areas of the New World. The nature of the toxin remains unclear. In addition to lipases and several glycosidases, extracts of salivary glands of the Australian froghopper Eoscarta carnifex (F.) were found to contain high levels of catalase. The insect catalase was shown to inhibit plant peroxidase in vitro; peroxidases are induced by wounding and are central to many of the major injury responses of the plant. We hypothesise that the role of the salivary catalase in E. carnifex may be in scavenging peroxide, thus suppressing the plant injury response.

scholarly journals Role of Homodimerization of Human Cytomegalovirus DNA Polymerase Accessory Protein UL44 in Origin-Dependent DNA Replication in Cells

2008 ◽  
Vol 82 (24) ◽  
pp. 12574-12579 ◽  
Author(s):  
Elisa Sinigalia ◽  
Gualtiero Alvisi ◽  
Beatrice Mercorelli ◽  
Donald M. Coen ◽  
Gregory S. Pari ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Human Cytomegalovirus ◽  
Nuclear Localization ◽  
Accessory Protein ◽  
C Terminus ◽  
Cellular Context ◽  
In Cells

ABSTRACT The presumed processivity subunit of human cytomegalovirus (HCMV) DNA polymerase, UL44, forms homodimers. The dimerization of UL44 is important for binding to DNA in vitro; however, whether it is also important for DNA replication in a cellular context is unknown. Here we show that UL44 point mutants that are impaired for dimerization, but not for nuclear localization or interaction with the C terminus of the polymerase catalytic subunit, are not capable of supporting HCMV oriLyt-dependent DNA replication in cells. These data suggest that the disruption of UL44 homodimers could represent a novel anti-HCMV strategy.

scholarly journals Differential phosphorylation signals control endocytosis of GPR15

2017 ◽  
Vol 28 (17) ◽  
pp. 2267-2281 ◽  
Author(s):  
Yukari Okamoto ◽  
Sojin Shikano
Keyword(s):  
Surface Density ◽  
Functional Role ◽  
Control Cell ◽  
Phosphorylation Site ◽  
Hek293 Cells ◽  
C Terminus ◽  
Differential Phosphorylation ◽  
G Protein Coupled

GPR15 is an orphan G protein–coupled receptor (GPCR) that serves for an HIV coreceptor and was also recently found as a novel homing receptor for T-cells implicated in colitis. We show that GPR15 undergoes a constitutive endocytosis in the absence of ligand. The endocytosis was clathrin dependent and partially dependent on β-arrestin in HEK293 cells, and nearly half of the internalized GPR15 receptors were recycled to the plasma membrane. An Ala mutation of the distal C-terminal Arg-354 or Ser-357, which forms a consensus phosphorylation site for basophilic kinases, markedly reduced the endocytosis, whereas phosphomimetic mutation of Ser-357 to Asp did not. Ser-357 was phosphorylated in vitro by multiple kinases, including PKA and PKC, and pharmacological activation of these kinases enhanced both phosphorylation of Ser-357 and endocytosis of GPR15. These results suggested that Ser-357 phosphorylation critically controls the ligand-independent endocytosis of GPR15. The functional role of Ser-357 in endocytosis was distinct from that of a conserved Ser/Thr cluster in the more proximal C-terminus, which was responsible for the β-arrestin– and GPCR kinase–dependent endocytosis of GPR15. Thus phosphorylation signals may differentially control cell surface density of GPR15 through endocytosis.

scholarly journals Structural basis of the interplay between α-synuclein and Tau in regulating pathological amyloid aggregation

2020 ◽  
Vol 295 (21) ◽  
pp. 7470-7480 ◽  
Author(s):  
Jinxia Lu ◽  
Shengnan Zhang ◽  
Xiaojuan Ma ◽  
Chunyu Jia ◽  
Zhenying Liu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Direct Interaction ◽  
Structural Basis ◽  
Amyloid Aggregation ◽  
C Terminus ◽  
Amyloid Fibrillation

Amyloid aggregation of pathological proteins is closely associated with a variety of neurodegenerative diseases, and α-synuclein (α-syn) deposition and Tau tangles are considered hallmarks of Parkinson's disease and Alzheimer's disease, respectively. Intriguingly, α-syn and Tau have been found to co-deposit in the brains of individuals with dementia and parkinsonism, suggesting a potential role of cross-talk between these two proteins in neurodegenerative pathologies. Here we show that monomeric α-syn and the two variants of Tau, Tau23 and K19, synergistically promote amyloid fibrillation, leading to their co-aggregation in vitro. NMR spectroscopy experiments revealed that α-syn uses its highly negatively charged C terminus to directly interact with Tau23 and K19. Deletion of the C terminus effectively abolished its binding to Tau23 and K19 as well as its synergistic effect on promoting their fibrillation. Moreover, an S129D substitution of α-syn, mimicking C-terminal phosphorylation of Ser129 in α-syn, which is commonly observed in the brains of Parkinson's disease patients with elevated α-syn phosphorylation levels, significantly enhanced the activity of α-syn in facilitating Tau23 and K19 aggregation. These results reveal the molecular basis underlying the direct interaction between α-syn and Tau. We proposed that this interplay might contribute to pathological aggregation of α-syn and Tau in neurodegenerative diseases.

Thymoquinone and its nanoformulation attenuate colorectal and breast cancers and alleviate doxorubicin-induced cardiotoxicity

Nanomedicine ◽  
2021 ◽  
Author(s):  
Ali H El-Far ◽  
Taher A Salaheldin ◽  
Kavitha Godugu ◽  
Noureldien HE Darwish ◽  
Shaker A Mousa
Keyword(s):  
Xenograft Model ◽  
Double Emulsion ◽  
Tumor Model ◽  
Breast Cancers ◽  
Anti Cancer ◽  
Xenograft Tumor Model ◽  
Average Size ◽  
Hct116 Cells

Aim: To investigate the anti-cancer potential of thymoquinone (TQ) and TQ nanoparticles (TQ-NPs) and their protection against doxorubicin (DOX)-induced cardiotoxicity. Methods: TQ-NPs were prepared by double emulsion method and characterized. The efficacy of TQ and TQ-DOX was studied against HCT116 and MDA-MB-231-Luc cancer cell lines in vitro and in a xenograft tumor model. Results: TQ and TQ + DOX increased Bax levels in HCT116 cells and decreased Bcl2 levels in MDA-MB-231-Luc cells. In the xenograft model, the TQ-NPs, with an average size of 218 nm, in combination with DOX, significantly reduced tumor size. The combination of TQ or TQ-NPs with DOX significantly reduced DOX-induced cardiotoxicity. Conclusion: Data suggest the promising role of TQ and TQ-NPs alone and with DOX for anti-cancer and cardiac protection benefits.

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