Alternative titles; symbols
HGNC Approved Gene Symbol: WIPI1
Cytogenetic location: 17q24.2 Genomic coordinates (GRCh38): 17:68,421,281-68,457,496 (from NCBI)
WD40 repeat proteins are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins, such as WIPI1, have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids (Proikas-Cezanne et al., 2004).
By screening a liver cDNA expression library for the ability to inhibit p53 (TP53; 191170), followed by RT-PCR of testis mRNA, Proikas-Cezanne et al. (2004) cloned 2 splice variants of WIPI1, which they designated WIPI1-alpha and WIPI1-beta. The deduced full-length WIPI1-alpha protein contains 7 WD-like repeats, conserved and invariant hydrophobic and polar residues, 2 invariant arginines that mediate phospholipid interaction, and 2 LxxLL motifs for nuclear receptor interaction. Northern blot analysis detected ubiquitous expression of an approximately 2.0-kb transcript. Highest expression was in testis, heart, and skeletal muscle. A 7.0-kb transcript was also ubiquitously expressed. RNA dot blot analysis confirmed ubiquitous expression of WIPI1. Within specific brain regions, expression was highest in adult cerebellum.
By live cell imaging of COS-7 cells, Jeffries et al. (2004) found that mammalian WIPI49 moved through the same set of endosomal membranes as that followed by mannose-6-phosphate receptor (MPR) (see IGF2R; 147280). Consistent with this, WIPI49 was enriched in clathrin (see 603531)-coated vesicles. Overexpression of WIPI49 disrupted the function of the MPR pathway, whereas expression of a double point mutant unable to bind phosphoinositides had no effect. Suppression of WIPI49 by interfering RNA indicated that WIPI49 is required for normal endosomal organization and distribution of IGF2R. Jeffries et al. (2004) concluded that WIPI49 is a regulatory component of the endosomal and MPR pathway and that its function is dependent upon the phosphoinositide-binding properties of its WD40 domain.
Using an in vitro protein binding assay, Proikas-Cezanne et al. (2004) found that WIPI1-alpha interacted with androgen receptor (AR; 313700), estrogen receptor (ESR1; 133430), and the retinoic acid receptors RAR (see 180240) and RXR (see 180245). The interactions were independent of ligand binding. Endogenous WIPI1 colocalized in part with an autophagosomal marker at punctate cytoplasmic structures in human melanoma cells. When autophagy was induced by amino acid deprivation, WIPI1 accumulated in large cup-shaped, vesicular, and lasso-like structures in the cytoplasm. Inhibition of phosphatidylinositol 3-kinase (see 601232) activity abolished the formation of these WIPI1-containing structures. Proikas-Cezanne et al. (2004) also found that expression of WIPI1 was aberrantly regulated in several human tumors.
By genomic sequence analysis, Proikas-Cezanne et al. (2004) mapped the WIPI1 gene to chromosome 17q24.3.
Jeffries, T. R., Dove, S. K., Michell, R. H., Parker, P. J. PtdIns-specific MPR pathway association of a novel WD40 repeat protein, WIPI49. Molec. Biol. Cell 15: 2652-2663, 2004. [PubMed: 15020712] [Full Text: https://doi.org/10.1091/mbc.e03-10-0732]
Proikas-Cezanne, T., Waddell, S., Gaugel, A., Frickey, T., Lupas, A., Nordheim, A. WIPI-1-alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 23: 9314-9325, 2004. [PubMed: 15602573] [Full Text: https://doi.org/10.1038/sj.onc.1208331]