WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome.

Abstract

Autophagy is a pivotal cytoprotective process that secures cellular homeostasis, fulfills essential roles in development, immunity and defence against pathogens, and determines the lifespan of eukaryotic organisms. However, autophagy also crucially contributes to the development of age-related human pathologies, including cancer and neurodegeneration. Macroautophagy (hereafter referred to as autophagy) clears the cytoplasm by stochastic or specific cargo recognition and destruction, and is initiated and executed by autophagy related (ATG) proteins functioning in dynamical hierarchies to form autophagosomes. Autophagosomes sequester cytoplasmic cargo material, including proteins, lipids and organelles, and acquire acidic hydrolases from the lysosomal compartment for cargo degradation. Prerequisite and essential for autophagosome formation is the production of phosphatidylinositol 3-phosphate (PtdIns3P) by phosphatidylinositol 3-kinase class III (PI3KC3, also known as PIK3C3) in complex with beclin 1, p150 (also known as PIK3R4; Vps15 in yeast) and ATG14L. Members of the human WD-repeat protein interacting with phosphoinositides (WIPI) family play an important role in recognizing and decoding the PtdIns3P signal at the nascent autophagosome, and hence function as autophagy-specific PtdIns3P-binding effectors, similar to their ancestral yeast Atg18 homolog. The PtdIns3P effector function of human WIPI proteins appears to be compromised in cancer and neurodegeneration, and WIPI genes and proteins might present novel targets for rational therapies. Here, we summarize the current knowledge on the roles of the four human WIPI proteins, WIPI1-4, in autophagy. This article is part of a Focus on Autophagosome biogenesis. For further reading, please see related articles: 'ERES: sites for autophagosome biogenesis and maturation?' by Jana Sanchez-Wandelmer et al. (J. Cell Sci. 128, 185-192) and 'Membrane dynamics in autophagosome biogenesis' by Sven R. Carlsson and Anne Simonsen (J. Cell Sci. 128, 193-205).

• Authors: Tassula Proikas-Cezanne, Zsuzsanna Takacs, Pierre Dönnes, Oliver Kohlbacher
• Journal: Journal of cell science (J Cell Sci) Vol. 128 Issue 2 Pg. 207-17 (Jan 15 2015) ISSN: 1477-9137 [Electronic] England
• PMID: 25568150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2015. Published by The Company of Biologists Ltd.

Chemical References

• ATG14 protein, human
• Adaptor Proteins, Vesicular Transport
• Apoptosis Regulatory Proteins
• Autophagy-Related Proteins
• BECN1 protein, human
• Beclin-1
• Carrier Proteins
• Membrane Proteins
• Nuclear Proteins
• PI3KCA protein, human
• Phosphatidylinositol Phosphates
• Transcription Factors
• WIPI1 protein, human
• phosphatidylinositol 3-phosphate
• Class III Phosphatidylinositol 3-Kinases
• PIK3R4 protein, human
• Vacuolar Sorting Protein VPS15

Topics

• Adaptor Proteins, Vesicular Transport (metabolism)
• Apoptosis Regulatory Proteins (genetics)
• Autophagy (genetics)
• Autophagy-Related Proteins
• Beclin-1
• Carrier Proteins (metabolism)
• Class III Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Humans
• Membrane Proteins (genetics, metabolism)
• Nuclear Proteins (metabolism)
• Phagosomes (genetics, metabolism)
• Phosphatidylinositol Phosphates (genetics, metabolism)
• Transcription Factors (metabolism)
• Vacuolar Sorting Protein VPS15 (metabolism)