Human WIPI β‐propeller function in autophagy and neurodegeneration

Abstract

The four human WIPI β‐propellers, WIPI1 through WIPI4, belong to the ancient PROPPIN family and fulfill scaffold functions in the control of autophagy. In this context, WIPI β‐propellers function as PI3P effectors during autophagosome formation and loss of WIPI function negatively impacts autophagy and contributes to neurodegeneration. Of particular interest are mutations in WDR45, the human gene that encodes WIPI4. Sporadic WDR45 mutations are the cause of a rare human neurodegenerative disease called BPAN, hallmarked by high brain iron accumulation. Here, we discuss the current understanding of the functions of human WIPI β‐propellers and address unanswered questions with a particular focus on the role of WIPI4 in autophagy and BPAN.

Autophagy—from yeast to humans: Thirty years of molecular autophagy

“…In this context, the human WIPI genes encoding PI3P-binding b-propellers that evolved from the ancestral yeast Atg18 [34,35] have been identified in 2004 to be aberrantly expressed in human cancer and to fulfill important roles in autophagy [36]. Their functions as PI3P effectors in autophagy and consequences of human WIPI gene mutations causing rare forms of neurodegeneration, as found initially for WDR45/WIPI4 [37,38], are summarized here by Proikas-Cezanne et al [39]. The special role of autophagy in fighting more common forms of neurodegenerative diseases is highlighted by Ryan and Rubinsztein [22], a pioneer in unrevealing the functional connection between autophagy and neurodegeneration [40].…”