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

IF 7.4 1区 生物学 Q1 CELL BIOLOGY Journal of Cell Biology Pub Date : 2024-10-07 Epub Date: 2024-07-15 DOI:10.1083/jcb.202402035
Kieop Park, Aastha Garde, Siddharthan B Thendral, Adam W J Soh, Qiuyi Chi, David R Sherwood
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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.

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新的脂质合成和极化的前酰化推动细胞侵入基底膜。
为了突破基底膜,细胞在发育和癌变过程中会使用大型、瞬时、特化的富脂膜突起。在秀丽隐杆线虫锚细胞(AC)入侵过程中,我们利用实时成像、内源蛋白标记和细胞特异性 RNAi 技术证明,在入侵之前,脂质生成 SREBP 转录因子 SBP-1 驱动脂肪酸合成酶 POD-2 和 FASN-1 的表达。我们还发现,以脂肪酸为底物的磷脂生产酶 LPIN-1 和鞘磷脂合成酶 SMS-1,可产生溶酶体储存,从而构建 AC 的侵袭性突起,SMS-1 还可促进脂筏分区 ZMP-1 基质金属蛋白酶的突起定位。最后,我们发现,HMG-CoA 还原酶 HMGR-1 能生成用于前炔化的异丙肾上腺素,它能定位到 ER 并富集在 AC 侵袭前沿的过氧物酶体中,最后一种跨膜前炔化酶 ICMT-1 能定位到内质网出口位点,这些位点能动态极化,为突起的形成提供前炔化 GTP 酶。这些结果共同揭示了脂肪生成与极化脂质前酰化系统之间的协作,这种协作推动了侵袭性突起的形成。
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来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
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