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Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival

Webster, Christopher M. ; Pino, Elizabeth C. ; Carr, Christopher E. ; Wu, Lianfeng ; Zhou, Ben ; Cedillo, Lucydalila ; Kacergis, Michael C. ; Curran, Sean P. ; Soukas, Alexander A.

Cell reports (Cambridge), 2017-07, Vol.20 (3), p.627-640 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival
Autor: Webster, Christopher M. ; Pino, Elizabeth C. ; Carr, Christopher E. ; Wu, Lianfeng ; Zhou, Ben ; Cedillo, Lucydalila ; Kacergis, Michael C. ; Curran, Sean P. ; Soukas, Alexander A.
Assuntos: amino-acyl tRNA synthetases ; AMP-Activated Protein Kinases - genetics ; AMP-Activated Protein Kinases - metabolism ; AMPK ; Animals ; C. elegans ; Caenorhabditis elegans - genetics ; Caenorhabditis elegans - metabolism ; Caenorhabditis elegans Proteins - genetics ; Caenorhabditis elegans Proteins - metabolism ; fat ; Genome-Wide Association Study ; lipid ; metabolism ; nutrient deprivation ; proteasome ; Proteostasis - physiology ; proteostatis ; starvation survival
É parte de: Cell reports (Cambridge), 2017-07, Vol.20 (3), p.627-640
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These authors contributed equally.
Descrição: 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. [Display omitted] •Opposing proteostasis pathways regulate C. elegans fat and starvation survival•Extended starvation survival with ARS RNAi requires elevated proteasome activity•Proteasome RNAi shortens starvation survival and blocks AMPK activation•AMPK is the critical determinant of starvation survival with altered proteostasis Using a genome-wide screen for fat regulatory genes in C. elegans, Webster et al. define a proteostasis-AMPK signaling axis that is central to organismal starvation defenses. The results suggest that enhanced survival under elevated proteasome activity is due to AMPK activation and not to increased fuel availability.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival

Webster, Christopher M. ; Pino, Elizabeth C. ; Carr, Christopher E. ; Wu, Lianfeng ; Zhou, Ben ; Cedillo, Lucydalila ; Kacergis, Michael C. ; Curran, Sean P. ; Soukas, Alexander A.

United States: Elsevier Inc

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