The role of TRPMLs in endolysosomal trafficking and function

Abstract

Members of the Transient Receptor Potential-Mucolipin (TRPML) constitute a family of evolutionarily conserved cation channels that function predominantly in endolysosomal vesicles. Whereas loss-of-function mutations in human TRPML1 were first identified as being causative for the lysosomal storage disease, Mucolipidosis type IV, most mammals also express two other TRPML isoforms called TRPML2 and TRPML3. All three mammalian TRPMLs as well as TRPML related genes in other species including Caenorhabditis elegans and Drosophila exhibit overlapping functional and biophysical properties. The functions of TRPML proteins include roles in vesicular trafficking and biogenesis, maintenance of neuronal development, function, and viability, and regulation of intracellular and organellar ionic homeostasis. Biophysically, TRPML channels are non-selective cation channels exhibiting variable permeability to a host of cations including Na(+), Ca(2+), Fe(2+), and Zn(2+), and are activated by a phosphoinositide species, PI(3,5)P2, that is mostly found in endolysosomal membranes. Here, we review the functional and biophysical properties of these enigmatic cation channels, which represent the most ancient and archetypical TRP channels.

Keywords: Autophagy; Ca(2+); Endolysosomal; Endosomal; Late-endosomal; Lysosomal; ML4; MLIV; Mucolipidosis type IV; Mucolipins; TRP channels; TRPML.

Figure 1. Topology of TRPML1 and MLIV-causing mutations that lead to codon change

TRPML1 is predicted to consist of six transmembrane domains (green barrels). Reported MLIV-causing mutations cause changes to the amino acid residues located in both loops and transmembrane regions. Missense mutations causing amino acid substitution are indicated in blue circles. Mutations causing premature stop codon (X) or in-frame deletion (Δ) are indicated in red circles. N and C denote amino-terminus and carboxyl terminus respectively.

Figure 2. Biological functions of TRPMLs in different cellular compartments

TRPML localizes to endolysosomes and facilitates Ca²⁺-dependent heterotypic fusion between amphisomes and lysosomes resulting in lysosomal degradation of endocytosed and autophagic material, which provides free amino acids for activation of the MTORC1. MTORC1 activation reduces lysosomal biogenesis via TFEB and promotes lysosome regeneration from autolysosomes. TRPML present on lysosome membrane is also responsible for triggering Ca²⁺-dependent lysosomal exocytosis, which in turn delivers TRPML to the plasma membrane.