The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span

Jiao, Rubin; Postnikoff, Spike D. L.; Harkness, Troy A. A.; Arnason, Terra

doi:10.1074/jbc.m115.647032

Cited by 15 publications

(21 citation statements)

References 73 publications

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“…Enhanced SNF1-mediated respiration by CR is also consistent with the activation of the Snf1 pathway that occurs in mutants that increase replicative life span through enhanced turnover of Mig1 (68), suggesting that SNF1 activation is a common feature of both CLS and RLS extension. Consistent with this result, deletion of SNF1 or the SIP2 ␤-subunit shortens RLS (69,70). Interestingly, Snf1 can also negatively impact RLS when Sip2 is acetylated, although this works independently of caloric restriction (71).…”

Section: Snf1 Mediates Life Span Extension By Crsupporting

confidence: 68%

Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

Wierman

Maqani

Strickler

et al. 2017

Molecular and Cellular Biology

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AMP-activated protein kinase (AMPK) and the homologous yeast SNF1 complex are key regulators of energy metabolism that counteract nutrient deficiency and ATP depletion by phosphorylating multiple enzymes and transcription factors that maintain energetic homeostasis. AMPK/SNF1 also promotes longevity in several model organisms, including yeast. Here we investigate the role of yeast SNF1 in mediating the extension of chronological life span (CLS) by caloric restriction (CR). We find that SNF1 activity is required throughout the transition of log phase to stationary phase (diauxic shift) for effective CLS extension. CR expands the period of maximal SNF1 activation beyond the diauxic shift, as indicated by Sak1-dependent T210 phosphorylation of the Snf1 catalytic ␣-subunit. A concomitant increase in ADP is consistent with SNF1 activation by ADP in vivo. Downstream of SNF1, the Cat8 and Adr1 transcription factors are required for full CR-induced CLS extension, implicating an alternative carbon source utilization for acetyl coenzyme A (acetyl-CoA) production and gluconeogenesis. Indeed, CR increased acetyl-CoA levels during the diauxic shift, along with expression of both acetyl-CoA synthetase genes ACS1 and ACS2. We conclude that CR maximizes Snf1 activity throughout and beyond the diauxic shift, thus optimizing the coordination of nucleocytosolic acetyl-CoA production with massive reorganization of the transcriptome and respiratory metabolism. KEYWORDS Snf1, AMPK, aging, yeast, caloric restriction, ADP, diauxic shift, acetyl-CoA A lthough each eukaryotic species suffers from its own set of age-related maladies, characteristics of the aging process at a cellular level are well conserved, including mitochondrial dysfunction, inefficient turnover of damaged proteins and organelles, accumulated reactive oxygen species (ROS) damage, and gradual breakdown of chromatin structure (reviewed in reference 1). Given the variety of the cellular components involved, it is astounding that any single intervention can alleviate the deterioration of all these processes. Caloric restriction (CR), however, slows the onset of aging-related pathologies and extends life span in almost every model organism tested, ranging from yeast to mammals (reviewed in reference 2). Some mechanistic commonalities for CR have emerged, including upregulation of cellular autophagy, increased mitochondrial respiration, protective oxidative stress responses, and decreased protein synthesis (reviewed in reference 3). The majority of these processes are regulated by a series of highly conserved nutrient signaling pathways, including the AMP-activated protein kinase (AMPK) signaling pathway (4).AMPK is the eukaryotic cell's primary energy sensor, regulating metabolism and other downstream processes while interacting with other signaling pathways (5). Experimental evidence for AMPK as a mediator of the CR longevity response is mounting. In Caenorhabditis elegans, AMPK is activated and required for life span extension under certain CR regimens (6, 7). I...

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Section: Snf1 Mediates Life Span Extension By Crsupporting

confidence: 68%

Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

Wierman

Maqani

Strickler

et al. 2017

Molecular and Cellular Biology

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“…1x10 5 cells from logarithmically growing cultures of each transformation set was repeatedly spotted down the glucose gradient of the slant plates 11, grown at 30°C until colonies were visible, and scanned. Freshly prepared warm liquid X-Gal agarose overlay medium 38 was layered to completely cover cells, solidified and incubated at 30°C and images scanned again after color development.…”

Section: Methodsmentioning

confidence: 99%

The ubiquitin-conjugating enzyme, Ubc1, indirectly regulates SNF1 kinase activity via Forkhead-dependent transcription

et al. 2016

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The SNF1 kinase in Saccharomyces cerevisiae is an excellent model to study the regulation and function of the AMP-dependent protein kinase (AMPK) family of serine-threonine protein kinases. Yeast discoveries regarding the regulation of this non-hormonal sensor of metabolic/environmental stress are conserved in higher eukaryotes, including poly-ubiquitination of the α-subunit of yeast (Snf1) and human (AMPKα) that ultimately effects subunit stability and enzyme activity. The ubiquitin-cascade enzymes responsible for targeting Snf1 remain unknown, leading us to screen for those that impact SNF1 kinase function. We identified the E2, Ubc1, as a regulator of SNF1 kinase function. The decreased Snf1 abundance found upon deletion of Ubc1 is not due to increased degradation, but instead is partly due to impaired SNF1 gene expression, arising from diminished abundance of the Forkhead 1/2 proteins, previously shown to contribute to SNF1 transcription. Ultimately, we report that the Fkh1/2 cognate transcription factor, Hcm1, fails to enter the nucleus in the absence of Ubc1. This implies that Ubc1 acts indirectly through transcriptional effects to modulate SNF1 kinase activity.

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“…AMPK activation is reported to extend the lifespan of lower organisms, including Caenorhabditis elegans (Chen et al, 2013), Drosophila (Stenesen et al, 2013), and yeast (Jiao et al, 2015). However, the role of AMPK in mammalian cellular senescence and aging process is controversial.…”

Section: Discussionmentioning

confidence: 99%

Absence of AMPKα2 accelerates cellular senescence via p16 induction in mouse embryonic fibroblasts

Ding

Chen

Okon

et al. 2016

The International Journal of Biochemistry & Cell Biology

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Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK), an energy gauge and redox sensor, delays aging process. However, the molecular mechanisms by which AMPKα isoform regulates cellular senescence remain largely unknown. The aim of this study was to determine if AMPKα deletion contributes to the accelerated cell senescence by inducing p16INK4A (p16) expression thereby arresting cell cycle. The markers of cellular senescence, cell cycle proteins, and reactive oxygen species (ROS) were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J), AMPKα1, or AMPKα2 homozygous deficient (AMPKα1−/−, AMPKα2−/−) mice by Western blot and cellular immunofluorescence staining, as well as immunohistochemistry (IHC) in skin tissue of young and aged mice. Deletion of AMPKα2, the minor isoform of AMPKα, but not AMPKα1 in high-passaged MEFs led to spontaneous cell senescence demonstrated by accumulation of senescence-associated-β-galactosidase (SA-β-gal) staining and foci formation of heterochromatin protein 1 homolog gamma (HP1γ). It was shown here that AMPKα2 deletion upregulates cyclin-dependent kinase (CDK) inhibitor, p16, which arrests cell cycle. Furthermore, AMPKα2 null cells exhibited elevated ROS production. Interestingly, knockdown of HMG box-containing protein 1 (HBP1) partially blocked the cellular senescence of AMPKα2-deleted MEFs via the reduction of p16. Finally, dermal cells senescence, including fibroblasts senescence evidenced by the staining of p16, HBP1, and Ki-67, in the skin of aged AMPKα2−/− mice was enhanced when compared with that in wild type mice. Taken together, our results suggest that AMPKα2 isoform plays a fundamental role in anti-oxidant stress and anti-senescence.

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The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span

Cited by 15 publications

References 73 publications

Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway

The ubiquitin-conjugating enzyme, Ubc1, indirectly regulates SNF1 kinase activity via Forkhead-dependent transcription

Absence of AMPKα2 accelerates cellular senescence via p16 induction in mouse embryonic fibroblasts

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