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葡萄糖限制驱动甲羟戊酸代谢的空间重排。

Glucose restriction drives spatial reorganization of mevalonate metabolism.

机构信息

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, United States.

Department of Biological Sciences, Wayne State University, Detroit, United States.

出版信息

Elife. 2021 Apr 7;10:e62591. doi: 10.7554/eLife.62591.

DOI:10.7554/eLife.62591
PMID:33825684
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8057812/
Abstract

Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. Both spatial retention of HMGCRs and increased mevalonate pathway flux during AGR is dependent on NVJ tether Nvj1. Furthermore, we demonstrate that HMGCRs associate into high-molecular-weight assemblies during AGR in an Nvj1-dependent manner. Loss of Nvj1-mediated HMGCR partitioning can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting the association of HMGCRs in high molecular weight assemblies. Loss of HMGCR compartmentalization perturbs yeast growth following glucose starvation, indicating it promotes adaptive metabolic remodeling. Collectively, we propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site.

摘要

真核生物将代谢途径分隔到细胞内的区域，但细胞器间接触在组织代谢反应中的作用仍知之甚少。在这里，我们表明，酵母在急性葡萄糖限制（AGR）下会对其甲羟戊酸途径进行代谢重塑，这种重塑在核-液泡连接（NVJ）处具有空间协调性。NVJ 作为一个代谢平台，通过选择性保留 HMG-CoA 还原酶（HMGCRs），以 Upc2 依赖的方式驱动甲羟戊酸途径的通量。AGR 期间 HMGCRs 的空间保留和甲羟戊酸途径通量的增加都依赖于 NVJ 连接蛋白 Nvj1。此外，我们证明 HMGCRs 在 AGR 期间以 Nvj1 依赖的方式组装成高分子量复合物。人工多聚化 HMGCRs 可以绕过 Nvj1 介导的 HMGCR 分配损失，表明 NVJ 区室化通过促进 HMGCRs 在高分子量复合物中的组装来增强甲羟戊酸途径的通量。HMGCR 区室化的丧失会干扰酵母在葡萄糖饥饿后的生长，表明它促进了适应性代谢重塑。总之，我们提出了一种非典型的机制，通过在细胞器间接触位点对限速 HMGCR 酶进行空间区室化来调节甲羟戊酸代谢。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/c085ebe167ae/elife-62591-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/12539e733743/elife-62591-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/297cdcce94f1/elife-62591-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/815abffc4b95/elife-62591-fig5.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/1983943a002d/elife-62591-fig6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/ea9fc2732046/elife-62591-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/c085ebe167ae/elife-62591-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/12539e733743/elife-62591-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/85a36e61036a/elife-62591-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/e0f2b976b016/elife-62591-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/8bf16b59cb10/elife-62591-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/e0f748751925/elife-62591-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/297cdcce94f1/elife-62591-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/815abffc4b95/elife-62591-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/c636b3add589/elife-62591-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/1983943a002d/elife-62591-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/6087f19b43bd/elife-62591-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/d24670ba1396/elife-62591-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/ea9fc2732046/elife-62591-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0498/8057812/c085ebe167ae/elife-62591-resp-fig1.jpg

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