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).
Highlights
IntroductionAutophagy is a cytoprotective mechanism involving the degradation of proteins, lipids and organelles in the lysosomal
Autophagy is a cytoprotective mechanism involving the degradation of proteins, lipids and organelles in the lysosomal compartment
Evidence suggests that WIPI1, WIPI2 and WIPI4 function as essential and non-redundant PtdIns3P effectors downstream of PI3KC3-mediated PtdIns3P production at the onset of autophagy
Summary
Autophagy is a cytoprotective mechanism involving the degradation of proteins, lipids and organelles in the lysosomal. ATG proteins are regulated by conserved nutrient and energy-dependent signaling cascades that crucially involve the mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) (Fig. 2C). Both mTOR and AMPK control the Unc51-like kinases ULK1 and ULK2 (Meijer and Codogno, 2011; Mizushima, 2010; Russell et al, 2014). Nutrient availability activates protein synthesis and cell growth through the mTOR complex 1 (mTORC1), an essential switch towards anabolic pathways. PI3KC3 in complex with beclin 1, p150 ( known as PIK3R4; Vps in yeast) and ATG14L translocates to the initiation site for autophagosome formation, with ATG14L playing a crucial role
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
