De novo lipid synthesis and polarized prenylation drives cell invasion through basement membrane

Abstract

SummaryInvasive cells form large, specialized protrusions to break through basement membrane (BM) matrix barriers. Park et al., reveal a crucial requirement for de novo lipid synthesis and a dynamic polarizing prenylation system to rapidly construct invasive protrusions that breach BMs. To breach basement membrane (BM), cells in development and cancer use large, transient, specialized lipid-rich membrane protrusions. Using live imaging, endogenous protein tagging, and cell-specific RNAi during C. elegans anchor cell (AC) invasion, we demonstrate that the lipogenic SREBP transcription factor SBP-1 drives expression of the fatty acid synthesis enzymes POD-2 and FASN-1 prior to invasion. We show that phospholipid producing LPIN-1 and sphingomyelin synthase SMS-1, which use fatty acids as substrates, produce lysosome stores that build the ACs invasive protrusion, and that SMS-1 also promotes protrusion localization of the lipid raft partitioning ZMP-1 matrix metalloproteinase. Finally, we discover that the endoplasmic reticulum (ER)-associated HMG-CoA reductase HMGR-1, which generates isoprenoids for prenylation, enriches at the AC invasive front, and that the final ER prenylation enzyme, ICMT-1, localizes to ER exit sites that dynamically polarize to deliver prenylated GTPases for protrusion formation. Together, these results reveal a collaboration between lipogenesis and a polarized lipid prenylation system that drives invasive protrusion formation.