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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.
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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 = 11â12) 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 = 13â15) 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 = 14â16) 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 = 15â16) 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 = 8â9) 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.
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