Two-pore channels at the intersection of endolysosomal membrane traffic

Abstract

Two-pore channels (TPCs) are ancient members of the voltage-gated ion channel superfamily that localize to acidic organelles such as lysosomes. The TPC complex is the proposed target of the Ca2+-mobilizing messenger NAADP, which releases Ca2+ from these acidic Ca2+ stores. Whereas details of TPC activation and native ion permeation remain unclear, a consensus has emerged around their function in regulating endolysosomal trafficking. This role is supported by recent proteomic data showing that TPCs interact with proteins controlling membrane organization and dynamics, including Rab GTPases and components of the fusion apparatus. Regulation of TPCs by PtdIns(3,5)P2 and/or NAADP (nicotinic acid adenine dinucleotide phosphate) together with their functional and physical association with Rab proteins provides a mechanism for coupling phosphoinositide and trafficking protein cues to local ion fluxes. Therefore, TPCs work at the regulatory cross-roads of (patho)physiological cues to co-ordinate and potentially deregulate traffic flow through the endolysosomal network. This review focuses on the native role of TPCs in trafficking and their emerging contributions to endolysosomal trafficking dysfunction.

Figure 1. TPCs regulate membrane traffic by integrating Ca^{2 +}, phosphoinositide and Rab cues

Schematic representation showing topology of (cylinders) and Ca^{2 +} flux through (black circles) TPCs (green), TRPML1 and P2X receptors (yellow). TRPMLs are regulated by the phosphoinositide, PtdIns(3,5)P₂ (left). P2X receptors are regulated by Rab proteins (right). TPCs are regulated by both PtdIns(3,5)P₂ and Rabs (centre).

Figure 2. Converging traffic on TPC interactors

Schematic representation highlighting the congruence between TPC interactors reported by Grimm et al. [53] within the Lin-Moshier et al. [44] dataset. Network nodes represent individual candidates identified in both datasets (purple, inner) or individual datasets {Grimm et al. [53] (blue), Lin-Moshier et al. [44] (red, outer)}. For example, 12 proteins (labelled) are identical in both datasets. Nodes are clustered into families circumferentially, with decreasing representation of candidate number per family clockwise. Only four candidates from the Grimm et al. [53] analysis were not represented in the Lin-Moshier et al. [44] dataset (10:00), highlighting the congruence between reports. Functional associations are predicted using FunCoup [26] and node size reflects summation of known protein-–protein interaction and predicted functional associations (green spokes).