Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Warsi J
,
Hosseinzadeh Z
,
Elvira B
,
Pelzl L
,
Shumilina E
,
Zhang DE
,
Lang KS
,
Lang PA
,
Lang F
.
???displayArticle.abstract??? USP18 (Ubiquitin-like specific protease 18) is an enzyme cleaving ubiquitin from target proteins. USP18 plays a pivotal role in antiviral and antibacterial immune responses. On the other hand, ubiquitination participates in the regulation of several ion channels and transporters. USP18 sensitivity of transporters has, however, never been reported. The present study thus explored, whether USP18 modifies the activity of the peptide transporters PEPT1 and PEPT2, and whether the peptide transporters are sensitive to the ubiquitin ligase Nedd4-2. To this end, cRNA encoding PEPT1 or PEPT2 was injected into Xenopus laevis oocytes without or with additional injection of cRNA encoding USP18. Electrogenic peptide (glycine-glycine) transport was determined by dual electrode voltage clamp. As a result, in Xenopus laevis oocytes injected with cRNA encoding PEPT1 or PEPT2, but not in oocytes injected with water or with USP18 alone, application of the dipeptide gly-gly (2 mM) was followed by the appearance of an inward current (Igly-gly). Coexpression of USP18 significantly increased Igly-gly in both PEPT1 and PEPT2 expressing oocytes. Kinetic analysis revealed that coexpression of USP18 increased maximal Igly-gly. Conversely, overexpression of the ubiquitin ligase Nedd4-2 decreased Igly-gly. Coexpression of USP30 similarly increased Igly-gly in PEPT1 expressing oocytes. In conclusion, USP18 sensitive cellular functions include activity of the peptide transporters PEPT1 and PEPT2.
???displayArticle.pubmedLink???
26046984
???displayArticle.pmcLink???PMC4457862 ???displayArticle.link???PLoS One
Fig 2. Coexpression of USP18 increases maximal electrogenic peptide transport in PEPT1-expressing Xenopus laevis oocytes.Arithmetic means ± SEM (n = 11–12) of Igly-gly as a function of glycine-glycine concentration in Xenopus laevis oocytes expressing PEPT1 without (black squares), or with (black circles) additional coexpression of wild type USP18. *(p<0.05) indicates statistically significant difference from the absence of USP18.
Fig 3. Coexpression of Nedd4-2 decreases electrogenic peptide transport in PEPT1-expressing Xenopus laevis oocytes.A: Representative original tracings showing Igly-gly in Xenopus laevis oocytes injected with water (a), expressing PEPT1 alone (b) or with USP18 (c), Nedd4-2 (d), or with USP18 and Nedd4-2 (e). B: Arithmetic means ± SEM (n = 13–15) of Igly-gly in Xenopus laevis oocytes injected with water (striped bar) or expressing PEPT1 without (white bar) or with USP18 (black bar), with Nedd4-2 (light grey bar), or with USP18 and Nedd4-2 (dark grey bar). *(p<0.05) indicates statistically significant difference from oocytes expressing PEPT1 alone.
Fig 4. Coexpression of USP30 increases electrogenic peptide transport in PEPT1-expressing Xenopus laevis oocytes.A: Representative original tracings showing Igly-gly in Xenopus laevis oocytes injected with water (a), expressing USP30 alone (b) or expressing PEPT1 without (c) or with additional coexpression of wild type USP30 (d). B: Arithmetic means ± SEM (n = 14–16) of Igly-gly in Xenopus laevis oocytes injected with water (striped bar), or expressing USP30 alone (grey bar) or expressing PEPT1 without (white bar) or with (black bar) USP30. ** (p<0.01) indicates statistically significant difference from the absence of USP30.
Fig 5. Effect of USP18 on PEPT1 in absence and presence of Actinomycin D.Arithmetic means ± SEM (n = 15–16) of Igly-gly in Xenopus oocytes injected PEPT1 without (white bar) or with (black bar) wild type USP18 in the absence (left bars) and presence (right bars) of 50 nM Actinomycin D 72 hours prior to measurement. *(p<0.05) indicates statistically significant difference from the absence of USP18.
Fig 6. Coexpression of USP18 increases electrogenic peptide transport in PEPT2-expressing Xenopus laevis oocytes.A: Representative original tracings showing Igly-gly in Xenopus laevis oocytes injected with water (a) or expressing USP18 alone (b) or expressing PEPT2 without (c) or with additional coexpression of wild type USP18 (d). B: Arithmetic means ± SEM (n = 8–9) of Igly-gly in Xenopus oocytes injected with water (striped bar), expressing USP18 alone (grey bar), or expressing PEPT2 without (white bar) or with (black bar) wild type USP18. **(p<0.01) indicates statistically significant difference from the absence of USP18.
Fig 1. Coexpression of USP18 increases electrogenic peptide transport in PEPT1-expressing Xenopus laevis oocytes.
A: Representative original tracings showing Igly-gly in Xenopus laevis oocytes injected with water (a), expressing USP18 alone (b) or expressing PEPT1 without (c) or with additional coexpression of wild type USP18 (d). B: Arithmetic means ± SEM (n = 12–18) of Igly-gly in Xenopus laevis oocytes injected with water (striped bar), or expressing USP18 alone (grey bar) or expressing PEPT1 without (white bar) or with (black bar) USP18. C: Representative original tracings showing glycine-glycine (2 mM)—induced current (Igly-gly) in Xenopus laevis oocytes injected with (a) 10 ng, (b) 15ng, or (c) 20ng cRNA encoding PEPT1. D: Arithmetic means ± SEM (n = 9–10) of Igly-gly in Xenopus laevis oocytes injected with 10 ng (striped bar) or 15 ng (grey bar) or 20 ng (black bar) cRNA encoding PEPT1. *** (p<0.001) indicates statistically significant difference from the absence of USP18.
Ait-Ali,
Functional analysis of the porcine USP18 and its role during porcine arterivirus replication.
2009, Pubmed
Ait-Ali,
Functional analysis of the porcine USP18 and its role during porcine arterivirus replication.
2009,
Pubmed
Almilaji,
Upregulation of the creatine transporter Slc6A8 by Klotho.
2014,
Pubmed
,
Xenbase
Alteheld,
Alanylglutamine dipeptide and growth hormone maintain PepT1-mediated transport in oxidatively stressed Caco-2 cells.
2005,
Pubmed
Ayyadurai,
PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis.
2013,
Pubmed
Baines,
Kinases as targets for ENaC regulation.
2013,
Pubmed
Boehmer,
The peptide transporter PEPT2 is targeted by the protein kinase SGK1 and the scaffold protein NHERF2.
2008,
Pubmed
,
Xenbase
Bongiorno,
Regulation of voltage-gated ion channels in excitable cells by the ubiquitin ligases Nedd4 and Nedd4-2.
2011,
Pubmed
Brandsch,
Transport of drugs by proton-coupled peptide transporters: pearls and pitfalls.
2009,
Pubmed
Burkart,
Two independent mechanisms promote expression of an N-terminal truncated USP18 isoform with higher DeISGylation activity in the nucleus.
2012,
Pubmed
Burkart,
Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-λ and elevated secretion of Cxcl10.
2013,
Pubmed
Cunningham,
USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria.
2015,
Pubmed
Dauphinee,
Contribution of increased ISG15, ISGylation and deregulated type I IFN signaling in Usp18 mutant mice during the course of bacterial infections.
2014,
Pubmed
Duex,
Usp18 regulates epidermal growth factor (EGF) receptor expression and cancer cell survival via microRNA-7.
2011,
Pubmed
Duex,
RNA interference screen identifies Usp18 as a regulator of epidermal growth factor receptor synthesis.
2009,
Pubmed
Eaton,
Regulation of epithelial sodium channel trafficking by ubiquitination.
2010,
Pubmed
Elvira,
SPAK and OSR1 dependent down-regulation of murine renal outer medullary K channel ROMK1.
2014,
Pubmed
,
Xenbase
Fezai,
Negative regulation of the creatine transporter SLC6A8 by SPAK and OSR1.
2014,
Pubmed
,
Xenbase
Francois-Newton,
USP18 establishes the transcriptional and anti-proliferative interferon α/β differential.
2012,
Pubmed
François-Newton,
USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response.
2011,
Pubmed
Gonzalez,
An oligopeptide transporter is expressed at high levels in the pancreatic carcinoma cell lines AsPc-1 and Capan-2.
1998,
Pubmed
Hong,
USP18 is crucial for IFN-γ-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity.
2014,
Pubmed
Honke,
Usp18 driven enforced viral replication in dendritic cells contributes to break of immunological tolerance in autoimmune diabetes.
2013,
Pubmed
Hosseinzadeh,
Upregulation of peptide transporters PEPT1 and PEPT2 by Janus kinase JAK2.
2013,
Pubmed
,
Xenbase
Ingersoll,
The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease.
2012,
Pubmed
Inoue,
Regulation of human peptide transporter 1 (PEPT1) in gastric cancer cells by anticancer drugs.
2005,
Pubmed
Kamal,
Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity.
2008,
Pubmed
Kim,
The level of hepatitis B virus replication is not affected by protein ISG15 modification but is reduced by inhibition of UBP43 (USP18) expression.
2008,
Pubmed
Kim,
Novel combination markers for predicting survival in patients with muscle invasive bladder cancer: USP18 and DGCR2.
2014,
Pubmed
Laedermann,
Ubiquitylation of voltage-gated sodium channels.
2014,
Pubmed
Lang,
Regulation of Orai1/STIM1 by the kinases SGK1 and AMPK.
2012,
Pubmed
Liu,
USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex.
2013,
Pubmed
Malakhov,
UBP43 (USP18) specifically removes ISG15 from conjugated proteins.
2002,
Pubmed
Malhotra,
Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon-β treatment.
2013,
Pubmed
Manini,
The DeISGylase USP18 limits TRAIL-induced apoptosis through the regulation of TRAIL levels: Cellular levels of TRAIL influences responsiveness to TRAIL-induced apoptosis.
2013,
Pubmed
Meredith,
Review. The mammalian proton-coupled peptide cotransporter PepT1: sitting on the transporter-channel fence?
2009,
Pubmed
,
Xenbase
Miranda,
Regulation of receptors and transporters by ubiquitination: new insights into surprisingly similar mechanisms.
2007,
Pubmed
Mitsuoka,
Inhibition of oligopeptide transporter suppress growth of human pancreatic cancer cells.
2010,
Pubmed
Munoz,
Up-regulation of Kir2.1 (KCNJ2) by the serum & glucocorticoid inducible SGK3.
2014,
Pubmed
,
Xenbase
Murray,
Knockdown of USP18 increases α 2a interferon signaling and induction of interferon-stimulating genes but does not increase antiviral activity in Huh7 cells.
2011,
Pubmed
Nakamura,
Pharmacogenetics of intestinal absorption.
2008,
Pubmed
Newstead,
Towards a structural understanding of drug and peptide transport within the proton-dependent oligopeptide transporter (POT) family.
2011,
Pubmed
Pakladok,
PIKfyve sensitivity of hERG channels.
2013,
Pubmed
,
Xenbase
Pieri,
The apical (hPepT1) and basolateral peptide transport systems of Caco-2 cells are regulated by AMP-activated protein kinase.
2010,
Pubmed
Potu,
Identification of USP18 as an important regulator of the susceptibility to IFN-alpha and drug-induced apoptosis.
2010,
Pubmed
Rexhepaj,
PI3 kinase and PDK1 in the regulation of the electrogenic intestinal dipeptide transport.
2010,
Pubmed
Rexhepaj,
Stimulation of electrogenic glucose transport by glycogen synthase kinase 3.
2010,
Pubmed
,
Xenbase
Richer,
Impact of Usp18 and IFN signaling in Salmonella-induced typhlitis.
2011,
Pubmed
Ritchie,
Role of ISG15 protease UBP43 (USP18) in innate immunity to viral infection.
2004,
Pubmed
Rotin,
Role of the ubiquitin system in regulating ion transport.
2011,
Pubmed
Rubio-Aliaga,
Peptide transporters and their roles in physiological processes and drug disposition.
2008,
Pubmed
Santin,
USP18 is a key regulator of the interferon-driven gene network modulating pancreatic beta cell inflammation and apoptosis.
2012,
Pubmed
Sarasin-Filipowicz,
Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43.
2009,
Pubmed
Schwer,
Cloning and characterization of a novel human ubiquitin-specific protease, a homologue of murine UBP43 (Usp18).
2000,
Pubmed
Shahidul Makki,
Ubiquitin specific protease 18 (Usp18) is a WT1 transcriptional target.
2013,
Pubmed
Snyder,
Down-regulating destruction: phosphorylation regulates the E3 ubiquitin ligase Nedd4-2.
2009,
Pubmed
Soundararajan,
Organization of the ENaC-regulatory machinery.
2012,
Pubmed
Stokes,
TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD.
2006,
Pubmed
Strutz-Seebohm,
A common structural component for β-subunit mediated modulation of slow inactivation in different KV channels.
2013,
Pubmed
,
Xenbase
Sun,
Functional and molecular expression of the proton-coupled oligopeptide transporters in spleen and macrophages from mouse and human.
2013,
Pubmed
Tai,
Expression profile and functional activity of peptide transporters in prostate cancer cells.
2013,
Pubmed
Terada,
Recent advances in structural biology of peptide transporters.
2012,
Pubmed
Tsume,
Enhanced cancer cell growth inhibition by dipeptide prodrugs of floxuridine: increased transporter affinity and metabolic stability.
2008,
Pubmed
Warsi,
Regulation of ClC-2 activity by SPAK and OSR1.
2014,
Pubmed
,
Xenbase
Warsi,
SPAK dependent regulation of peptide transporters PEPT1 and PEPT2.
2014,
Pubmed
,
Xenbase
Warsi,
Downregulation of peptide transporters PEPT1 and PEPT2 by oxidative stress responsive kinase OSR1.
2014,
Pubmed
,
Xenbase
Xu,
USP18 restricts PRRSV growth through alteration of nuclear translocation of NF-κB p65 and p50 in MARC-145 cells.
2012,
Pubmed
Yang,
Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions.
2010,
Pubmed
Yang,
Transport and utilization of arginine and arginine-containing peptides by rat alveolar macrophages.
2002,
Pubmed
Yarandi,
Diverse roles of leptin in the gastrointestinal tract: modulation of motility, absorption, growth, and inflammation.
2011,
Pubmed
Yui,
Cross-presentation of malaria antigen by brain microvessels: why CD8(+) T cells are critical for the pathogenesis of experimental cerebral malaria.
2013,
Pubmed
