The role of PI3P phosphatases in the regulation of autophagy

Abstract

Autophagy initiation is strictly dependent on phosphatidylinositol 3-phosphate (PI3P) synthesis. PI3P production is under tight control of PI3Kinase, hVps34, in complex with Beclin-1. Mammalian cells express several PI3P phosphatases that belong to the myotubularin family. Even though some of them have been linked to serious human diseases, their cellular function is largely unknown. Two recent studies indicate that PI3P metabolism involved in autophagy initiation is further regulated by the PI3P phosphatases Jumpy and MTMR3. Additional pools of PI3P, upstream of mTOR and on the endocytic pathway, may modulate autophagy indirectly, suggesting that other PI3P phosphatases might be involved in this process. This review sums up our knowledge on PI3P phosphatases and discusses the recent progress on their role in autophagy.

Figure 1. Myotubularin family: activity and different members with their domains

hVps34 catalyzes phosphatidylinositol (PI) phosphorylation at position 3 on inositol ring to form phosphatidylinositol 3-phosphate (PI3P). PI3P can be further phosphorylated by PYKfyve to generate PI3,5,P₂. Myotubularins remove 3-phosphate on PI3P and PI3,5P₂ resulting in generation of PI and PI5P, respectively. Nine active and six inactive phosphatases are present in humans. See text for domain description.

Figure 2. Intracellular PI3P pools and PI3P phosphatases in autophagy regulation

MTMR14 and MTMR3 inhibit autophagy by dephosphorylating PI3P involved in autophagosome formation. MTMR6 and MTMR7 depletions increase LC3-II via unknown mechanisms. Since MTMR6 regulates KCa3.1, we propose that MTMR6 might modulate autophagy by acting on Ca²⁺ influx. We speculate that some PI3P phosphatases might regulate autophagy by dephosphorylating pools of PI3P and/or PI3,5P₂ involved in Akt and mTOR activation (a and b), autolysosome formation/membrane recycling (c) and autophagosome transport (d) (see text and (52)). AP: autophagosome; AL: autolysosome. a.a.:amino-acids. In red: PI3P phosphatases inhibiting autophagy. IM: isolation membrane; In bold: PI3P phosphatases whose knockdown affect LC3-II level. Question marks indicate that the role of these pathways in regulating autophagy is speculative and remains to be investigated.