Molecular mechanisms underlying myotubularin-related phosphoinositide 3-phosphatase function in health and disease

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Phosphoinositides (PIs) are a minor class of short-lived membrane phospholipids that mediate crucial cellular and organismal functions. PI 3-phosphates can be produced at the cell surface during signalling, but are mainly found in the endolysosomal system. Turnover of PI 3-phosphates is accomplished by several types of PI phosphatases, most notably the myotubularin family (i.e. MTMs), which has been closely linked to human disease. The MTM family comprises 15 members that differ with respect to domain structure, presumed localization, and catalytic activity. Major questions related to MTM localization, function, and regulation remain unanswered. Based on our previous studies and preliminary results we hypothesize that the recruitment and activation of MTMRs and their complexes to endosomes or lysosomes is mediated by their association with proteins (e.g. Rabs) and is controlled by nutrient signals (e.g. via protein kinases or phosphatases). The overarching objectives of the proposed research therefore are to (i) define the nanoscale localization and function of the catalytically active MTMRs MTM1, R1, R2, R7, and R14, and of MTMR12 (i.e. the inactive binding partner of MTM1) (ii) to molecularly define the mechanisms by which these MTMRs undergo complex formation and associate with their recruitment factors (e.g. proteins), and, finally, (iii) to dissect the regulatory network that controls MTMR function in response to physiological or pathophysiological stimuli (e.g. starvation, lysosomal damage). We expect these studies to provide new insights into the physiological regulation of MTMR-based signaling and its interplay with nutrient signaling and, eventually cell metabolism and/ or cell stress. Such information is critical for the development of novel therapies to treat human diseases linked to MTMR dysfunction.