PP2A and CDK16 antagonistically regulate WIPI2B phosphorylation and neuronal autophagosome biogenesis

Area of Science:

• Cellular Biology
• Neuroscience
• Molecular Biology

Background:

• Autophagy is a vital cellular recycling process essential for maintaining homeostasis.
• Autophagosome biogenesis declines in aging primary neurons, impacting neuronal health.
• WIPI2B expression can restore autophagosome biogenesis, with its phosphorylation at serine 395 being critical.

Purpose of the Study:

• To identify regulators of WIPI2B S395 phosphorylation and their role in neuronal autophagy.
• To investigate the function of Protein Phosphatase 2A (PP2A) and CDK16 in the context of WIPI2B-mediated autophagy.

Main Methods:

• Utilized primary murine neurons and *Caenorhabditis elegans* models.
• Investigated protein-protein interactions and phosphorylation events in vitro and in vivo.
• Manipulated PP2A and CDK16 expression and observed effects on WIPI2B puncta and autophagosome biogenesis.

Main Results:

• Identified PP2A and CDK16 as key regulators of WIPI2B S395 phosphorylation.
• Demonstrated that PP2A and CDK16 function in the same genetic pathway as WIPI2B in *C. elegans*.
• Showed that PP2A and CDK16 directly modify WIPI2B S395 phosphorylation and colocalize with WIPI2B at autophagosomes in neurons.

Conclusions:

• PP2A and CDK16 regulate WIPI2B S395 phosphorylation, a critical step for neuronal autophagy.
• These findings elucidate a novel regulatory mechanism for autophagosome biogenesis in neurons, with implications for aging and neurodegeneration.