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)P2, 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)P2 3-phosphatase myotubularin gene is mutated in X-linked centronuclear myopathy, whereas its homologs MTMR2 and MTMR13 and the PtdIns(3,5)P2 5-phosphatase SAC3/FIG4 are implicated in Charcot–Marie–Tooth peripheral neuropathies. Mutations in the gene encoding the PtdIns3P5-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.
Highlights
Phosphoinositides (PIs) are lipid second messengers implicated in signal transduction and membrane trafficking
The PtdIns3P and PtdIns[3,5]P2 3-phosphatase myotubularin gene is mutated in X-linked centronuclear myopathy, whereas its homologs MTMR2 and MTMR13 and the PtdIns[3,5]P2 5-phosphatase SAC3/FIG4 are implicated in Charcot– Marie–Tooth peripheral neuropathies
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
Summary
Phosphoinositides (PIs) are lipid second messengers implicated in signal transduction and membrane trafficking. Cultured fibroblasts from pale tremor mice are filled with enlarged late endosomes/lysosomes and show a reduced level of PtdIns[3,5]P2 compared with wild type in apparent discrepancy with the PtdIns[3,5]P2 5-phosphatase function of SAC3 [50,51] This phenotype mimics PIP5K3/FAB1 suppression and is similar to FIG4-deficient yeast strains [52]. Overexpression of human MTMR2 in yeast leads to enlarged vacuoles and, in hypoosmotically stressed COS cells with increased levels of PtdIns[3,5]P2, MTMR2 is recruited to the membrane of vacuoles formed under these conditions [66,67] This redistribution of MTMR2 is dependent on its PH-GRAM domain, which has been proposed to bind PtdIns[3,5]P2 and/or PtdIns5P [68,69,70]. Defects in membrane remodeling could be the underlying cause of X-linked centronuclear myopathy
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