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.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

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."]
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: 20736310External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Validation: In vivo validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  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 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML2 Co-immunoprecipitation HEK293 Human Full-length (mutation in the pore region) Human Full-length (mutation in the pore region) 20736310
TRPML1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML3 Co-immunoprecipitation HEK293 Human Full-length (mutation in the pore region) Human Full-length (mutation in the pore region) 20736310
TRPML2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML1 Co-immunoprecipitation HEK293 Human Full-length (mutation in the pore region) Human Full-length (mutation in the pore region) 20736310
TRPML2 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML3 Co-immunoprecipitation HEK293 Human Full-length (mutation in the pore region) Human Full-length (mutation in the pore region) 20736310
TRPML3 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML1 Co-immunoprecipitation HEK293 Human Full-length (mutation in the pore region) Human Full-length (mutation in the pore region) 20736310
TRPML3 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML2 Co-immunoprecipitation HEK293 Human Full-length (mutation in the pore region) Human Full-length (mutation in the pore region) 20736310
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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