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Abstract
WIPIs are a conserved family of proteins with a characteristic 7-bladed β-propeller structure. They play a prominent role in autophagy, but also in other membrane trafficking processes. Mutations in human WIPI4 cause several neurodegenerative diseases. One of them is BPAN, a rare disease characterized by developmental delay, motor disorders, and seizures. Autophagy dysfunction is thought to play an important role in this disease but the precise pathological consequences of the mutations are not well established. The use of simple models such as the yeast Saccharomyces cerevisiae and the social amoeba Dictyostelium discoideum provides valuable information on the molecular and cellular function of these proteins, but also sheds light on possible pathways that may be relevant in the search for potential therapies. Here, we review the function of WIPIs as well as disease-causing mutations with a special focus on the information provided by these simple models.
Highlights
Degradation and recycling of cellular components are essential for cell homeostasis
The PtdIns3P generated at the autophagosome assembly site recruits a family of proteins called WIPIs (WD-repeat protein Interacting with phosphoinositides), known as PROPPINs, which are necessary for the subsequent recruitment of other autophagic proteins
One of the proteins recruited by WIPIs is Atg2 in yeast (ATG2A/ATG2B in mammalian cells), a lipid transport protein that appears to be responsible for autophagosome membrane elongation through lipid transport from the endoplasmic reticulum (ER) (Maeda et al, 2019; Osawa et al, 2019, 2020; Valverde et al, 2019)
Summary
Degradation and recycling of cellular components are essential for cell homeostasis. Autophagy (from the Greek, “self-eating”) includes several pathways that deliver different types of cargos to lysosomes for degradation. Autophagosome biogenesis is a highly regulated process involving different stages: induction, lipidation, and elongation of the autophagosome membrane ( known as the isolation membrane or phagophore), vesicle closure, and fusion with lysosomes. These steps are controlled by protein complexes formed mainly by the so-called Atg proteins. The nutritional and energetic status of cells regulates autophagy through two master regulators, TORC1 and AMPK (Hindupur et al, 2015).
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