Endosomal phosphoinositides and human diseases

Abstract

Phosphoinositides (PIs) are lipid second messengers implicated in signal transduction and membrane trafficking. Seven distinct PIs can be synthesized by phosphorylation of the inositol ring of phosphatidylinositol (PtdIns), and their metabolism is accurately regulated by PI kinases and phosphatases. Two of the PIs, PtdIns3P and PtdIns(3,5)P(2), are present on intracellular endosomal compartments, and several studies suggest that they have a role in membrane remodeling and trafficking. We refer to them as 'endosomal PIs'. An increasing number of human genetic diseases including myopathy and neuropathies are associated to mutations in enzymes regulating the turnover of these endosomal PIs. The PtdIns3P and PtdIns(3,5)P(2) 3-phosphatase myotubularin gene is mutated in X-linked centronuclear myopathy, whereas its homologs MTMR2 and MTMR13 and the PtdIns(3,5)P(2) 5-phosphatase SAC3/FIG4 are implicated in Charcot-Marie-Tooth peripheral neuropathies. Mutations in the gene encoding the PtdIns3P 5-kinase PIP5K3/PIKfyve have been found in patients affected with François-Neetens fleck corneal dystrophy. This review presents the roles of the endosomal PIs and their regulators and proposes defects of membrane remodeling as a common pathological mechanism for the corresponding diseases.

Figure 1. Endosomal PI structure, metabolism, subcellular localization and associated human diseases

A) Chemical structure of PtdIns that can be phosphorylated on position 3, 4 and/or 5. B) Interconversion of PtdIns3P and PtdIns(3,5)P₂ is catalyzed by kinases, PIK3C3 (VPS34 in Saccharomyces cerevisiae) and PIP5K3 (also called PIKfyve and FAB1 in S. cerevisiae), and phosphatases, SAC3 (FIG4 in S. cerevisiae) and myotubularins, including MTM1, MTMR2 and the inactive phosphatase MTMR13. Associated human diseases are shown in blue. C) Subcellular localization of PtdIns3P (in green) and PtdIns(3,5)P₂ (in red) are shown in the endocytic pathway: early endosomes, sorting endosomes, recycling endosomes for receptor recycling and MVBs/late endosomes and lysosomes for degradation. The localization of PtdIns(3,5)P₂ is hypothetical. Based on works performed in yeast, Drosophila, Caenorhabditis elegans and mammalian cells, PtdIns(3,5)P₂ should be present at the external membrane of late endosomes and at lysosomes. The destiny of lysosomes is not known but rather hypothetical based on the same studies.