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

Author:

Park Kieop1ORCID,Garde Aastha23ORCID,Thendral Siddharthan B.1ORCID,Soh Adam W.J.1ORCID,Chi Qiuyi1ORCID,Sherwood David R.1ORCID

Affiliation:

1. Duke University 1 Department of Biology, , Durham, NC, USA

2. Princeton University 2 Department of Molecular Biology, , Princeton, NJ, USA

3. Princeton University 3 Howard Hughes Medical Institute, , Princeton, NJ, USA

Abstract

To breach the basement membrane, cells in development and cancer use large, transient, specialized lipid-rich membrane protrusions. Using live imaging, endogenous protein tagging, and cell-specific RNAi during Caenorhabditis elegans anchor cell (AC) invasion, we demonstrate that the lipogenic SREBP transcription factor SBP-1 drives the 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 AC’s invasive protrusion, and that SMS-1 also promotes protrusion localization of the lipid raft partitioning ZMP-1 matrix metalloproteinase. Finally, we discover that HMG-CoA reductase HMGR-1, which generates isoprenoids for prenylation, localizes to the ER and enriches in peroxisomes at the AC invasive front, and that the final transmembrane prenylation enzyme, ICMT-1, localizes to endoplasmic reticulum 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.

Funder

Cancer Genomics Centre

National Institutes of Health

Office of Research Infrastructure Programs

Jane Coffin Childs Memorial Fund for Medical Research

Publisher

Rockefeller University Press

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