Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival
Organisms must execute metabolic defenses to survive nutrient deprivation. We performed a genome-wide RNAi screen in Caenorhabditis elegans to identify fat regulatory genes indispensable for starvation resistance. Here, we show that opposing proteostasis pathways are principal determinants of starva...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717308999 |
| _version_ | 1828485981849780224 |
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| author | Christopher M. Webster Elizabeth C. Pino Christopher E. Carr Lianfeng Wu Ben Zhou Lucydalila Cedillo Michael C. Kacergis Sean P. Curran Alexander A. Soukas |
| author_facet | Christopher M. Webster Elizabeth C. Pino Christopher E. Carr Lianfeng Wu Ben Zhou Lucydalila Cedillo Michael C. Kacergis Sean P. Curran Alexander A. Soukas |
| author_sort | Christopher M. Webster |
| collection | DOAJ |
| description | Organisms must execute metabolic defenses to survive nutrient deprivation. We performed a genome-wide RNAi screen in Caenorhabditis elegans to identify fat regulatory genes indispensable for starvation resistance. Here, we show that opposing proteostasis pathways are principal determinants of starvation survival. Reduced function of cytoplasmic aminoacyl tRNA synthetases (ARS genes) increases fat mass and extends starvation survival, whereas reduced proteasomal function reduces fat and starvation survival. These opposing pathways converge on AMP-activated protein kinase (AMPK) as the critical effector of starvation defenses. Extended starvation survival in ARS deficiency is dependent upon increased proteasome-mediated activation of AMPK. When the proteasome is inhibited, neither starvation nor ARS deficiency can fully activate AMPK, leading to greatly diminished starvation survival. Thus, activity of the proteasome and AMPK are mechanistically linked and highly correlated with starvation resistance. Conversely, aberrant activation of the proteostasis-AMPK axis during nutritional excess may have implications for obesity and cardiometabolic diseases. |
| first_indexed | 2024-12-11T09:25:06Z |
| format | Article |
| id | doaj.art-4b497a686e6442d89ac74faa349deb0e |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T09:25:06Z |
| publishDate | 2017-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-4b497a686e6442d89ac74faa349deb0e2022-12-22T01:13:11ZengElsevierCell Reports2211-12472017-07-0120362764010.1016/j.celrep.2017.06.068Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation SurvivalChristopher M. Webster0Elizabeth C. Pino1Christopher E. Carr2Lianfeng Wu3Ben Zhou4Lucydalila Cedillo5Michael C. Kacergis6Sean P. Curran7Alexander A. Soukas8Department of Medicine, Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USADepartment of Medicine, Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USADepartment of Earth, Atmospheric and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USADepartment of Medicine, Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USADepartment of Medicine, Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USADepartment of Medicine, Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USADepartment of Medicine, Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USALeonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USADepartment of Medicine, Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USAOrganisms must execute metabolic defenses to survive nutrient deprivation. We performed a genome-wide RNAi screen in Caenorhabditis elegans to identify fat regulatory genes indispensable for starvation resistance. Here, we show that opposing proteostasis pathways are principal determinants of starvation survival. Reduced function of cytoplasmic aminoacyl tRNA synthetases (ARS genes) increases fat mass and extends starvation survival, whereas reduced proteasomal function reduces fat and starvation survival. These opposing pathways converge on AMP-activated protein kinase (AMPK) as the critical effector of starvation defenses. Extended starvation survival in ARS deficiency is dependent upon increased proteasome-mediated activation of AMPK. When the proteasome is inhibited, neither starvation nor ARS deficiency can fully activate AMPK, leading to greatly diminished starvation survival. Thus, activity of the proteasome and AMPK are mechanistically linked and highly correlated with starvation resistance. Conversely, aberrant activation of the proteostasis-AMPK axis during nutritional excess may have implications for obesity and cardiometabolic diseases.http://www.sciencedirect.com/science/article/pii/S2211124717308999C. elegansfatlipidmetabolismnutrient deprivationstarvation survivalAMPKproteasomeamino-acyl tRNA synthetasesproteostatis |
| spellingShingle | Christopher M. Webster Elizabeth C. Pino Christopher E. Carr Lianfeng Wu Ben Zhou Lucydalila Cedillo Michael C. Kacergis Sean P. Curran Alexander A. Soukas Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival Cell Reports C. elegans fat lipid metabolism nutrient deprivation starvation survival AMPK proteasome amino-acyl tRNA synthetases proteostatis |
| title | Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival |
| title_full | Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival |
| title_fullStr | Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival |
| title_full_unstemmed | Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival |
| title_short | Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival |
| title_sort | genome wide rnai screen for fat regulatory genes in c elegans identifies a proteostasis ampk axis critical for starvation survival |
| topic | C. elegans fat lipid metabolism nutrient deprivation starvation survival AMPK proteasome amino-acyl tRNA synthetases proteostatis |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717308999 |
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