ferritinophagy-assessing-selective-degradation-iron-autophagy-human

Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts

Mutations in the autophagy gene WDR45/WIPI4 are the cause of beta-propeller-associated neurodegeneration (BPAN), a subtype of human diseases known as ...

Eberhard Karls University Tübingen

Human WIPI β-propellers function as PI3P effectors in autophagy, with WIPI4 and WIPI3 being able to link autophagy control by AMPK and TORC1 to the formation of autophagosomes. WIPI1, instead, assists WIPI2 in efficiently recruiting the ATG16L1 complex at the nascent autophagosome, which in turn promotes lipidation of LC3/GABARAP and autophagosome maturation. However, the specific role of WIPI1 and its regulation are unknown. Here, we discovered the ABL-ERK-MYC signalling axis controlling WIPI1. As a result of this signalling, MYC binds to the WIPI1 promoter and represses WIPI1 gene expression. When ABL-ERK-MYC signalling is counteracted, increased WIPI1 gene expression enhances the formation of autophagic membranes capable of migrating through tunnelling nanotubes to neighbouring cells with low autophagic activity. ABL-regulated WIPI1 function is relevant to lifespan control, as ABL deficiency in C. elegans increased gene expression of the WIPI1 orthologue ATG-18 and prolonged lifespan in a manner dependent on ATG-18. We propose that WIPI1 acts as an enhancer of autophagy that is physiologically relevant for regulating the level of autophagic activity over the lifespan.

The ABL-MYC axis controls WIPI1-enhanced autophagy in lifespan extension.

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.

Carmen J. Pastor-Maldonado

Interfaculty Institute of Cell Biology

Eberhard Karls University Tübingen

Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts

Carmen J. Pastor-Maldonado

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Eberhard Karls University Tübingen

Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts

Interfaculty Institute of Cell Biology