Cells adapt to extracellular acidic pH through TM9SF3-mediated PI(4,5)P₂ flop

Area of Science:

• Cell Biology
• Biochemistry
• Developmental Biology

Background:

• The plasma membrane (PM) controls cell-environment interactions via signaling pathways.
• The role of PM lipids, like phosphatidylinositol 4,5-bisphosphate (PIP2), in these responses is largely unknown.
• Extracellular environmental fluctuations necessitate cellular adaptation mechanisms.

Purpose of the Study:

• To investigate the role of PM lipids in cellular response to extracellular stimuli.
• To identify regulators of PIP2 dynamics in the plasma membrane.
• To understand the functional significance of PIP2 translocation during development.

Main Methods:

• Genome-wide screening to identify regulators of PIP2 translocation.
• Zebrafish gastrulation model to study cell migration and cytoskeletal organization.
• Analysis of PIP2 localization and TM9SF3 function under varying pH conditions.

Main Results:

• Extracellular acidification induces translocation of PIP2 from the inner to the outer leaflet of the PM.
• Transmembrane 9 superfamily 3 (TM9SF3) is identified as a key regulator of this PIP2 translocation.
• Loss of Tm9sf3 impairs collective cell migration in zebrafish due to defective PIP2-dependent cytoskeletal organization during gastrulation.

Conclusions:

• TM9SF3 mediates pH-dependent PIP2 translocation, enabling cells to adapt to low extracellular pH.
• Lipid topology changes, specifically PIP2 redistribution, represent a conserved mechanism for cellular environmental sensing.
• This lipid-based signaling pathway is critical for developmental processes like cell migration.