Jul 18 – 20, 2022
via Zoom
Asia/Hong_Kong timezone

Control of PI(4,5)P2 homeostasis via non-vesicular lipid transport regulated by PDZD-8 and TEX-2

Jul 20, 2022, 10:00 AM


Yasunori Saheki (National University of Singapore)


Zoom link: https://hkust.zoom.us/j/93318955512?pwd=bDVqbmk4VGRCTTlhN3VoN0RlMXplZz09
Meeting ID: 933 1895 5512
Passcode: 737042

Cellular membranes maintain unique lipid compositions that are important for their functional identity. PI(4,5)P2 is enriched in the plasma membrane where it contributes to local activation of key cellular events, including actomyosin contraction and cytokinesis. However, how cells prevent PI(4,5)P2 from accumulating in intracellular membrane compartments, despite constant intermixing and exchange of lipid membranes via membrane trafficking, remains poorly understood. Using the C. elegans early embryo as our model system, we show that the evolutionarily conserved lipid transfer proteins (PDZD-8 and TEX-2) and PI(4,5)P2 phosphatases (UNC-26/synaptojanin and OCRL-1) act together to prevent the build-up of PI(4,5)P2 on endosomal membranes. In the absence of these four proteins, large amounts of PI(4,5)P2 accumulate on endosomes, leading to embryonic lethality due to ectopic recruitment of proteins involved in actomyosin contractility. PDZD-8 localizes to sites of contact between the endoplasmic reticulum and late endosomes and regulates endosomal PI(4,5)P2 levels via its lipid harboring SMP domain. Accumulation of PI(4,5)P2 on endosomes is accompanied by impairment of their degradative capacity. Thus, cells use multiple redundant systems to maintain endosomal PI(4,5)P2 homeostasis. Mutations in human homologs of UNC-26 and OCRL-1 are linked to Parkinson’s disease and Lowe syndrome, respectively. Our study reveals an exciting possibility that manipulating the activity of the lipid transfer proteins may help alleviate disease progression in patients with dysfunction in these proteins.

Primary author

Yasunori Saheki (National University of Singapore)

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