Regulation of autophagy by phosphatidylinositol 3‐phosphate

Abstract

a b s t r a c tThe simple phosphoinositide phosphatidylinositol 3-phosphate (PI(3)P) has been known to have important functions in endocytic and phagocytic traffic, and to be required for the autophagic pathway. In all of these settings, PI(3)P appears to create platforms that serve to recruit specific effectors for membrane trafficking events. In autophagy, PI(3)P may form the platform for autophagosome biogenesis. Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Formation and consumption of PI(3)PPhosphoinositides (PI's) are formed by the phosphorylation of phosphatidylinositol (PI) on its inositol ring. With the exception of the 2 0 and 6 0 positions all free OH groups of the inositol ring can be phosphorylated. The unique functional role of each type of PI within the cell can be attributed to the arrangement of phosphate groups around the inositol ring. Phosphoinositide 3-kinases (PI3 kinases) are the enzymes responsible for phosphorylating the 3 0 OH-position of the inositol ring of PI, and three classes of these enzymes exist in cells [1,2] Class I PI3 kinases most commonly phosphorylate PI(4,5)P 2 at its 3 0 OH group to produce PI(3,4,5)P 2 (often referred to as PIP3). Class III PI3 kinases are the orthologues of the yeast vesicular protein-sorting protein Vps34, and these enzymes can only utilise PI as a substrate (Fig. 1). Class II PI3 Kinase can use PI, PI(4)P and PI(4,5)P 2 as substrates, with a strong preference for PI. It is likely that the type III enzyme is responsible for the majority of PI(3)P synthesis within cells, whereas the type II enzymes appear to be involved in specialised signal-dependent settings [3]. PI(3)P can be further phosphorylated by a 4 0 -kinase at its 4 0 -position to generate PI(3,4)P 2 (Fig. 1). Additionally, PI(3)P can be phosphorylated by a PI(3)P 5-kinase known as PIKfyve in mammals (Fab1p in yeast) to form PI(3,5)P 2 [4]. 3 0 Phosphatases that can act on PI(3)P include PTEN (phosphatase and tensin homologue) [5], myotubularin proteins such as Jumpy [6,7], and the yeast phosphatase, Sac1p [8]. Recognition of PI(3)P by specific protein domainsThe generation of PI's by PI3 kinases has been found to be responsible for a diverse array of cellular signalling events, often mediated by distinct proteins that can bind to PI's. Lipid binding can affect the localization, conformation and/or activity of PI-binding proteins, and two types of PI(3)P-binding domains have been reported. One is the FYVE domain (whose name reflects the first four proteins found to contain it: Fab1p,YOTB, Vac1p and Early Endosome Antigen 1) [9,10]. At present 37 FYVE domain containing proteins have been identified in humans. These domains are known to bind to PI(3)P with high affinity (K d = 50 nM) and they usually consist of approximately 65 amino acids with eight conserved cysteine residues. A hydrophobic loop in the FYVE domain initially interacts with the membrane in a non-specific manner. This leads to the subsequent exposure of a characteristic bas...

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