Heteromultimeric TRPML channel assemblies play a crucial role in the regulation of cell viability models and starvation-induced autophagy.
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.
Zeevi
David A
DA
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.
Lev
Shaya
S
Frumkin
Ayala
A
Minke
Baruch
B
Bach
Gideon
G
D001343:Autophagy; D002470:Cell Survival; D019281:Dimerization; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D050053:TRPM Cation Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C416674:MCOLN1 protein, human; C510642:MCOLN3 protein, human; C510641:Mcoln2 protein, human; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels