EMBO J. 2006 Dec 13;25(24):5659-69. Epub 2006 Nov 16.
The HECT ubiquitin ligase AIP4 regulates the cell surface expression of select TRP channels.
Wegierski, T., Hill, K., Schaefer, M., Walz, G.,
["Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, Freiburg 79106, Germany."]
["Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, Freiburg 79106, Germany."]
TRPV4 is a widely expressed member of the transient receptor potential (TRP) family that facilitates Ca(2+) entry into nonexcitable cells. TRPV4 is activated by several stimuli, but it is largely unknown how the activity of this channel is terminated. Here, we show that ubiquitination represents an important mechanism to control the presence of TRPV4 at the plasma membrane. Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. Consequently, the basal activity of TRPV4 is reduced despite an overall increase in TRPV4 levels. This mode of regulation is not limited to TRPV4. TRPC4, another member of the TRP channel family, is also strongly ubiquitinated in the presence of AIP4, leading to the increased intracellular localization of TRPC4 and the reduction of its basal activity. However, ubiquitination of several other TRP channels is not affected by AIP4, demonstrating that AIP4-mediated regulation is a unique property of select TRP channels.
PMID: 17110928

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Screening
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Experimental screening | Non-experimental screening | Reference | ||||||||
TRP channel construct | Interactor source | |||||||||
TRP channel | Interactor | Method | Species | Region | Species | Organ/tissue | Sample type | |||
TRPC6 |
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UBC | Inference | Prediction | 17110928 | |||||
TRPV4 |
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ITCH/AIP4 | Inference | Prediction | 17110928 | |||||
TRPV4 |
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UBC | Inference | Prediction | 17110928 |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)

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Validation: In vivo validation
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Assay with endogenous proteins | Assay with overexpressed proteins | Reference | ||||||||
Cell or tissue | Cell or tissue | TRP channel construct | Interactor construct | |||||||
TRP channel | Interactor | Method | Species | Region | Species | Region | ||||
TRPV4 |
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ITCH/AIP4 | Co-immunoprecipitation | HEK293T | Mouse | Full-length | Mouse | Full-length | 17110928 | |
TRPV4 |
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ITCH/AIP4 | Co-immunofluorescence staining | HEK293T | Mouse | Full-length | Mouse | Full-length | 17110928 |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)

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Functional consequence
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TRP channel | Interactor | Method | Post-translational modification | Subcellular trafficking | Activity | Reference | ||||||
TRPC6 |
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UBC | In vivo PTM assay | Ubiquitination | 17110928 | |||||||
TRPV4 |
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ITCH/AIP4 | Co-immunofluorescence staining | Decrease in plasma membrane level | 17110928 | |||||||
TRPV4 |
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UBC | In vivo PTM assay | Ubiquitination | 17110928 |
(
:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
