Structural analysis of the Rubicion:PI3KC3-C2 complex in endolysome maturation and autophagy
Year: 2024
Type: preprint
Abstract: Rubicon is a regulator of autophagy, the endolysosomal network (ELN), and exosomes that selectively antagonizes the class III phosphatidylinositol 3-kinase complex II (PI3KC3-C2). As a negative regulator of PI3KC3-C2, inhibition of Rubicon is considered a potential means to therapeutically upregulate autophagy and ELN to treat Parkinson’s disease and other conditions characterized by autophagic and ELN dysfunction. However, the mechanism underlying the strict specificity of Rubicon for the PI3KC3-C2 complex remains unclear, and the relationship between PI3KC3-C2 complex binding and the regulation of autophagy and the ELN has not been rigorously established. Here, we report the high-resolution cryo-electron microscopy structure of the PI3KC3-C2 in complex with Rubicon and compare it to refined cryo-EM structures of unbound PI3KC3-C2 and PI3KC3-C1. Rubicon binds directly to PI3KC3-C2 only via the BARA domain of the BECN1 subunit. The selectivity of Rubicon for the PI3KC3-C2 complex over the PI3KC3-C1 complex is attributed to a conformational change in the BECN1BARA domain induced by UVRAG, rather than to direct contacts with UVRAG or to direct antagonism by the ATG14 subunit of PI3KC3-C1. Targeted disruption of the Rubicon:PI3K3-C2 interaction enhances autophagic activity in human epithelial cells to levels comparable to those observed in Rubicon knockout (KO) cells, suggesting that suppressing the function of PI3K3-C2 is the predominant regulatory mechanism of Rubicon.
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Award: G314929196
OpenAlex ID: W7206171199
Cites:
Cited by:
Related to: