J Cell Sci. 2010 Sep 15;123(Pt 18):3112-24. doi: 10.1242/jcs.067330. Epub 2010 Aug 24.
Heteromultimeric TRPML channel assemblies play a crucial role in the regulation of cell viability models and starvation-induced autophagy.
Zeevi, D. A., Lev, S., Frumkin, A., Minke, B., Bach, G.,
["Monique and Jacques Roboh Department of Genetic Research, Institute of Medical Research Israel-Canada (IMRIC), Faculty of Medicine of the Hebrew University and Hadassah Hebrew University Hospital, Jerusalem 91120, Israel."]
["Monique and Jacques Roboh Department of Genetic Research, Institute of Medical Research Israel-Canada (IMRIC), Faculty of Medicine of the Hebrew University and Hadassah Hebrew University Hospital, Jerusalem 91120, Israel."]
The mucolipin (TRPML) subfamily of transient receptor potential (TRP) cation channels consists of three members that play various roles in the regulation of membrane and protein sorting along endo-lysosomal pathways. Loss-of-function mutations in TRPML1 cause the neurodegenerative lysosomal storage disorder, mucolipidosis type IV (MLIV), whereas a gain-of-function mutation in TRPML3 is principally implicated in the hearing-impaired and abnormally pigmented varitint-waddler mouse. Currently, TRPML2 is not implicated in any pathological disorder, but we have recently shown that it is a functional cation channel that physically interacts with TRPML1 and TRPML3 to potentially regulate lysosomal integrity. Here, we show that mutant TRPMLs heteromultimerize with other mutant and wild-type TRPMLs to regulate cell viability and starvation-induced autophagy, a process that mediates macromolecular and organellar turnover under cell starvation conditions. Heteromultimerization of dominant-negative TRPMLs with constitutively active TRPMLs rescues cells from the cytotoxic effects of TRPML constitutive activity. Moreover, dominant-negative TRPML1 channels, including a mutant channel directly implicated in MLIV pathology, also inhibit starvation-induced autophagy by interacting with and affecting native TRPML channel function. Collectively, our results indicate that heteromultimerization of TRPML channels plays a role in various TRPML-regulated mechanisms.
PMID: 20736310
 Screening
Validation: In vitro validation
Validation: In vivo validation
Characterization
Functional consequence
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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 | ||||
| TRPML1 |
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TRPML2 | Co-immunoprecipitation | HEK293 | Human | Full-length (mutation in the pore region) | Human | Full-length (mutation in the pore region) | 20736310 | |
| TRPML1 |
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TRPML3 | Co-immunoprecipitation | HEK293 | Human | Full-length (mutation in the pore region) | Human | Full-length (mutation in the pore region) | 20736310 | |
| TRPML2 |
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TRPML1 | Co-immunoprecipitation | HEK293 | Human | Full-length (mutation in the pore region) | Human | Full-length (mutation in the pore region) | 20736310 | |
| TRPML2 |
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TRPML3 | Co-immunoprecipitation | HEK293 | Human | Full-length (mutation in the pore region) | Human | Full-length (mutation in the pore region) | 20736310 | |
| TRPML3 |
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TRPML1 | Co-immunoprecipitation | HEK293 | Human | Full-length (mutation in the pore region) | Human | Full-length (mutation in the pore region) | 20736310 | |
| TRPML3 |
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TRPML2 | Co-immunoprecipitation | HEK293 | Human | Full-length (mutation in the pore region) | Human | Full-length (mutation in the pore region) | 20736310 | |
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)