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

磷酸肌苷（pi）是一类短寿命膜磷脂，介导重要的细胞和机体功能。pi3 -磷酸可以在信号传导过程中在细胞表面产生，但主要存在于内溶酶体系统中。PI 3-磷酸盐的周转是由几种类型的PI磷酸酶完成的，最显著的是肌管蛋白家族（即MTMs），它与人类疾病密切相关。MTM家族包括15个成员，这些成员在结构域结构、假定定位和催化活性方面有所不同。与MTM定位、功能和调控相关的主要问题仍未得到解答。根据我们之前的研究和初步结果，我们假设mtmr及其复合物在核内体或溶酶体中的募集和激活是通过它们与蛋白质（如Rabs）的结合介导的，并受营养信号（如通过蛋白激酶或磷酸酶）的控制。因此，提出的研究的总体目标是：(i)确定催化活性MTMRs MTM1， R1, R2， R7和R14以及MTMR12（即MTM1的无活性结合伙伴）的纳米级定位和功能；（ii）从分子上定义这些MTMRs经历复杂形成并与其招募因子（例如蛋白质）相关联的机制，最后，（iii）剖析在生理或病理生理刺激（如饥饿、溶酶体损伤）下控制MTMR功能的调控网络。我们希望这些研究能够为mtmr信号的生理调控及其与营养信号的相互作用以及最终的细胞代谢和/或细胞应激提供新的见解。这些信息对于开发治疗与MTMR功能障碍相关的人类疾病的新疗法至关重要。

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.