Glucose restriction drives spatial reorganization of mevalonate metabolism
© 2021, Rogers et al..
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.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
|---|---|
| Enthalten in: |
eLife - 10(2021) vom: 07. Apr. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Rogers, Sean [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 13.09.2021 Date Revised 24.09.2021 published: Electronic CommentIn: Elife. 2021 Jun 01;10:. - PMID 34061033 Citation Status MEDLINE |
|---|
| doi: |
10.7554/eLife.62591 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM323809758 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM323809758 | ||
| 003 | DE-627 | ||
| 005 | 20231225184957.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.7554/eLife.62591 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1079.xml |
| 035 | |a (DE-627)NLM323809758 | ||
| 035 | |a (NLM)33825684 | ||
| 035 | |a (PII)e62591 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Rogers, Sean |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Glucose restriction drives spatial reorganization of mevalonate metabolism |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 13.09.2021 | ||
| 500 | |a Date Revised 24.09.2021 | ||
| 500 | |a published: Electronic | ||
| 500 | |a CommentIn: Elife. 2021 Jun 01;10:. - PMID 34061033 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021, Rogers et al. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HMG-CoA Reductase | |
| 650 | 4 | |a S. cerevisiae | |
| 650 | 4 | |a cell biology | |
| 650 | 4 | |a lipid droplet | |
| 650 | 4 | |a mevalonate | |
| 650 | 4 | |a nucleus-vacuole junction | |
| 650 | 4 | |a sterol-ester | |
| 650 | 7 | |a Glucose |2 NLM | |
| 650 | 7 | |a IY9XDZ35W2 |2 NLM | |
| 650 | 7 | |a Mevalonic Acid |2 NLM | |
| 650 | 7 | |a S5UOB36OCZ |2 NLM | |
| 700 | 1 | |a Hariri, Hanaa |e verfasserin |4 aut | |
| 700 | 1 | |a Wood, N Ezgi |e verfasserin |4 aut | |
| 700 | 1 | |a Speer, Natalie Ortiz |e verfasserin |4 aut | |
| 700 | 1 | |a Henne, W Mike |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t eLife |d 2012 |g 10(2021) vom: 07. Apr. |w (DE-627)NLM221831460 |x 2050-084X |7 nnns |
| 773 | 1 | 8 | |g volume:10 |g year:2021 |g day:07 |g month:04 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.7554/eLife.62591 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 10 |j 2021 |b 07 |c 04 | ||