WIPI proteins: Biological functions and related syndromes

Abstract

WIPI (WD-repeat protein Interacting with PhosphoInositides) are important effectors in autophagy. These proteins bind phosphoinositides and recruit autophagy proteins. In mammals, there are four WIPI proteins: WIPI1, WIPI2, WIPI3 (WDR45B), and WIPI4 (WDR45). These proteins consist of a seven-bladed β-propeller structure. Recently, pathogenic variants in genes encoding these proteins have been recognized to cause human diseases with a predominant neurological phenotype. Defects in WIPI2 cause a disease characterized mainly by intellectual disability and variable other features while pathogenic variants in WDR45B and WDR45 have been recently reported to cause El-Hattab-Alkuraya syndrome and beta-propeller protein-associated neurodegeneration (BPAN), respectively. Whereas, there is no disease linked to WIPI1 yet, one study linked it neural tube defects (NTD). In this review, the role of WIPI proteins in autophagy is discussed first, then syndromes related to these proteins are summarized.

Keywords: WD repeat domain; WDR; WIPI; autophagy; neurodevelopment.

Figure 1

Summary of different steps of autophagy and role of WIPI proteins is illustrated. ULK1/2 and VPS34 complexes are involved in initiation and nucleation steps. The produced phosphatidylinositol 3-phosphate (PtdIns3P) pool recruit downstream autophagy proteins, including WIPI2 which recruits ATG16L complex for LC3 lipidation and autophagosome formation. WIPI4 binds to ATG2 and the ATG2-WIPI4 complex acts as a tethering factor for phagophore expansion. Finally, the expanding autophagosome closes and fuses with lysosomes.