PI Metabolism

Phosphatidylinositol (PI), a membrane phospholipid, can be reversibly phosphorylated at the 3, 4, and 5 positions of the inositol ring to generate seven phosphoinositides: phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4-phosphate (PI4P), phosphatidylinositol 5-phosphate (PI5P), phosphatidylinositol 3,4-bisphosphate PI(3,4)P2, phosphatidylinositol 4,5-bisphosphate PI(4,5)P2, phosphatidylinositol 3,5-bisphosphate PI(3,5)P2, and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). These seven phosphoinositides, which are heterogeneously distributed within cells, can serve as signature components of different intracellular compartment membranes and so help to mediate specificity of membrane interactions. Phosphoinositide levels are tightly regulated spatially and temporally by the action of various kinases and phosphatases whilst PI(4,5)P2 is also a substrate for phospholipase C. The differential localisation of each of these enzymes on specific compartment membranes ensures maintenance of the heterogeneous distribution of phosphoinositides despite the continuous membrane flow from one compartment to another.<br><br>PI is primarily synthesised in the endoplasmic reticulum from where the phospholipid is exported to other compartments via membrane traffic or via cytosolic phospholipid transfer proteins. Phosphorylation of PI to PI4P primarily occurs in the Golgi, where PI4P plays an important role in the biogenesis of transport vesicles such as the secretory vesicle involved in its transport to the plasma membrane. At this place, PI4P has a major function acting as a precursor of PI(4,5)P2, which is located predominantly at this membrane. PI(4,5)P2 binds and regulates a wide range of proteins that function on the cell surface and serves as a precursor for second messengers. Additionally, it helps define this membrane as a target for secretory vesicles, functions as a coreceptor in endocytic processes, and functions as a cofactor for actin nucleation.<br><br>At the plasma membrane, PI(4,5)P2 is further phosphorylated to PI(3,4,5)P3, another phosphoinositide with important signalling functions including stimulating cell survival and proliferation. The inositol 3-phosphatase, phosphatase and tensin homolog (PTEN) regenerates PI(4,5)P2, while the 5-phosphatases convert PI(3,4,5)P3 into the phosphoinositide, PI(3,4)P2, propagating the signal initiated by PI(3,4,5)P3. PI(3,4)P2 is further dephosphorylated in the endocytic pathway by inositol 4-phosphatases to PI3P, the signature phosphoinositide of the early endosomal compartment and a ligand for numerous endosomal proteins. However, the bulk of PI3P is generated directly in the endosomes by phosphorylation of PI. The subsequent endosomal phosphorylation of PI3P to PI(3,5)P2 is believed to generate docking sites for recruitment of cytosolic factors responsible for the control of outgoing traffic from the endosomes. The main localisation and function of the low abundance phosphoinositide PI5P, that can be generated by several pathways, remains to be determined (Krauss & Haucke 2007, Leventis & Grinstein 2010, Roth 2004, Gees et al. 2010, De Matteis & Godi 2004, van Meer et al. 2008, Vicinanza et al. 2008, Lemmon 2008, Kutaleladze 2010, Robinson & Dixon 2006, Blero et al. 2007, Liu & Bankaitis 2010, McCrea & De Camilli 2009, Vicinanza et al. 2008, Di Paolo & De Camilli, 2006).

磷脂酰肌醇（PI），一种膜磷脂，可在肌醇环的3、4和5位进行可逆磷酸化，从而生成七种磷脂酰肌醇：磷脂酰肌醇3磷酸（PI3P）、磷脂酰肌醇4磷酸（PI4P）、磷脂酰肌醇5磷酸（PI5P）、磷脂酰肌醇3,4-二磷酸PI(3,4)P2、磷脂酰肌醇4,5-二磷酸PI(4,5)P2、磷脂酰肌醇3,5-二磷酸PI(3,5)P2以及磷脂酰肌醇3,4,5-三磷酸（PI(3,4,5)P3）。这七种磷脂酰肌醇在细胞内呈异质性分布，可作为不同细胞内区室膜的特征成分，从而有助于介导膜相互作用的特异性。磷脂酰肌醇的水平受到各种激酶和磷脂酶的严格时空调控，而PI(4,5)P2也是磷脂酶C的底物。这些酶在特定区室膜上的不同定位确保了尽管膜从一区室流向另一区室存在持续流动，磷脂酰肌醇的异质性分布仍得以维持。<br><br>PI主要在内质网中合成，然后通过膜交通或通过细胞质磷脂转移蛋白将其磷脂输送到其他区室。PI磷酸化至PI4P主要发生在高尔基体中，其中PI4P在运输囊泡（如参与其向质膜的运输的分泌囊泡）的生物发生中发挥重要作用。在此处，PI4P的主要功能是作为PI(4,5)P2的前体，而PI(4,5)P2主要位于该膜上。PI(4,5)P2与多种蛋白结合并调节其在细胞表面的功能，作为第二信使的前体，并有助于定义该膜作为分泌囊泡的目标，在吞咽过程中作为核心受体，以及作为肌动蛋白核化的辅因子。<br><br>在质膜上，PI(4,5)P2进一步磷酸化为PI(3,4,5)P3，这是另一种具有重要信号功能的磷脂酰肌醇，包括刺激细胞存活和增殖。肌醇3磷酸酶、磷酸酶和张力蛋白同源物（PTEN）再生PI(4,5)P2，而5磷酸酶将PI(3,4,5)P3转化为磷脂酰肌醇，即PI(3,4)P2，从而传播由PI(3,4,5)P3引发的信号。PI(3,4)P2随后在吞咽途径中由肌醇4磷酸酶去磷酸化，转化为PI3P，这是早期内吞体区室的特征磷脂酰肌醇，也是多种内吞体蛋白的配体。然而，大部分PI3P是通过直接在囊泡中对PI进行磷酸化直接生成的。据信，PI3P在囊泡中的后续磷酸化至PI(3,5)P2可生成细胞质因子招募的停靠位点，这些因子负责控制从囊泡中输出的交通。低丰度磷脂酰肌醇PI5P的主要定位和功能，可以通过多种途径生成，仍有待确定（Krauss & Haucke 2007，Leventis & Grinstein 2010，Roth 2004，Gees et al. 2010，De Matteis & Godi 2004，van Meer et al. 2008，Vicinanza et al. 2008，Lemmon 2008，Kutaleladze 2010，Robinson & Dixon 2006，Blero et al. 2007，Liu & Bankaitis 2010，McCrea & De Camilli 2009，Vicinanza et al. 2008，Di Paolo & De Camilli, 2006）。