title: Heteromultimeric TRPML channel assemblies play a crucial role in the regulation of cell viability models and starvation-induced autophagy.
abstract: 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.
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Zeevi
authors.forename: Shaya
authors.initials: S
authors.lastname: Lev
authors.forename: Ayala
authors.initials: A
authors.lastname: Frumkin
authors.forename: Baruch
authors.initials: B
authors.lastname: Minke
authors.forename: Gideon
authors.initials: G
authors.lastname: Bach
mesh_terms: 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*
chemical_list: C416674:MCOLN1 protein, human; C510642:MCOLN3 protein, human; C510641:Mcoln2 protein, human; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels