Autophagy genes mediate the effect of calcineurin on life span in<i>C. elegans</i>

Dwivedi, Meenakshi; Song, Hyun-Ok; Ahnn, Joohong

doi:10.4161/auto.5.5.8157

Cited by 56 publications

(36 citation statements)

References 18 publications

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“…RCAN‐1 is typically studied as an inhibitor of calcineurin (Lee et al ., 2003a), implying that increased calcineurin activity should promote longevity. However, reduced calcineurin activity is reported to increase worm lifespan, mediated by increased autophagy (Dwivedi et al ., 2009). Studies reporting calcineurin inhibition by RCNs have often been conducted in the context of RCN overexpression, while in the normal range of physiological expression human and yeast RCN can either activate or inhibit calcineurin, depending on context (Hilioti et al ., 2004).…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

et al. 2017

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SummaryWe report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity‐correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu‐1), a neuronal leucine‐rich repeat protein (iglr‐1), a tetraspanin (tsp‐3), a regulator of calcineurin (rcan‐1), and a voltage‐gated calcium channel subunit (unc‐36). Knockdown of each gene extended healthspan without impairing reproduction. kynu‐1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu‐1, tsp‐3, and rcan‐1 are of particular interest for immediate follow‐up. kynu‐1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp‐3 is a novel modulator of hypoxic signaling and rcan‐1 is a context‐specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age‐associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow‐up.

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Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

et al. 2017

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“…39 Indeed, phosphatases have recently been linked to the autophagy pathway, such as several well-known phosphatases (PTEN, PPM1D/WIP1, PTPRS/PTPs, and PPP2CA), and newly identified phosphatases (PGAM5, SGPP1 [sphingosine-1-phosphate phosphatase 1] and calcineurin). 20,[40][41][42][43] However, none of these studies have directly linked the activity of phosphatases to ATG16L1 function. This study not only identified PPP1 as a phosphatase that directly dephosphorylates CSNK2-phosphorylated ATG16Ll, but also indicated that ATG16Ll binds to PPP1 Experiments were repeated at least 3 times.…”

Section: Discussionmentioning

confidence: 99%

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

Song¹,

Wang³

et al. 2015

Autophagy

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(2015) ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation, Autophagy, 11:8, 1308-1325, DOI: 10.1080/15548627.2015 Keywords: ATG16L1, autophagy, cardiomyocyte, casein kinase 2, protein phosphatase 1 Abbreviations: ACTB, actinb; AMPK, AMP activated protein kinase; ATG, autophagy-related; BCL2, B-cell CLL/lymphoma 2; BECN1/Beclin 1, autophagy related; CD, Crohn disease; CSNK2, casein kinase 2; GFP, green fluorescent protein; GNB2L1/ RACK1, guanine nucleotide binding protein (G protein)bpolypeptide 2-like 1; GST, glutathione S-transferase; H/R, hypoxia/reoxygenation; I/R, ischemia/reperfusion; LAD, left anterior descending; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; mRFP, monomeric red fluorescent protein; MTORC1, mechanistic target of rapamycin complex 1; NRVCs, neonatal rat ventricular cardiomyocytes; OA, okadaic acid; PE, phosphatidylethanolamine; PPP1, protein phosphatase 1; PPP2, protein phosphatase 2; PVDF, polyvinylidenedifluoride; SNP, single nucleotide polymorphism; SUPT20H/p38IP, suppressor of Ty 20 homolog (S. cerevisiae); TBB, 4,5,6,7-tetrabromobenzotriazole; lPP, l protein phosphatase.Recent studies have shown that the phosphorylation and dephosphorylation of ULK1 and ATG13 are related to autophagy activity. Although ATG16L1 is absolutely required for autophagy induction by affecting the formation of autophagosomes, the post-translational modification of ATG16L1 remains elusive. Here, we explored the regulatory mechanism and role of ATG16L1 phosphorylation for autophagy induction in cardiomyocytes. We showed that ATG16L1 was a phosphoprotein, because phosphorylation of ATG16L1 was detected in rat cardiomyocytes during hypoxia/ reoxygenation (H/R). We not only demonstrated that CSNK2 (casein kinase 2) phosphorylated ATG16L1, but also identified the highly conserved Ser139 as the critical phosphorylation residue for CSNK2. We further established that ATG16L1 associated with the ATG12-ATG5 complex in a Ser139 phosphorylation-dependent manner. In agreement with this finding, CSNK2 inhibitor disrupted the ATG12-ATG5-ATG16L1 complex. Importantly, phosphorylation of ATG16L1 on Ser139 was responsible for H/R-induced autophagy in cardiomyocytes, which protects cardiomyocytes from apoptosis. Conversely, we determined that wild-type PPP1 (protein phosphatase 1), but not the inactive mutant, associated with ATG16L1 and antagonized CSNK2-mediated phosphorylation of ATG16L1. Interestingly, one RVxF consensus site for PPP1 binding in the C-terminal tail of ATG16L1 was identified; mutation of this site disrupted its association with ATG16L1. Notably, CSNK2 also associated with PPP1, but ATG16L1 depletion impaired the interaction between CSNK2 and PPP1. Collectively, these data identify ATG16L1 as a bona fide physiological CSNK2 and PPP1 substrate, which reveals a novel molecular link from CSNK2 to activation of the autophagy-specific ATG12-ATG5-ATG16L1 complex and autoph...

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“…Calcineurin deficiency extends lifespan and enhances autophagy in the nematode. RNAi-mediated depletion of bec-1 and atg-7 genes suppresses lifespan extension in CaN mutants, indicating that autophagy is required for the longevity phenotype of calcineurin defective C. elegans strains (Dwivedi et al, 2009). …”

Section: Calcineurinmentioning

confidence: 99%

Autophagy and ageing: Insights from invertebrate model organisms

Lionaki

Markaki

Tavernarakis

2013

Ageing Research Reviews

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a b s t r a c tAgeing in diverse species ranging from yeast to humans is associated with the gradual, lifelong accumulation of molecular and cellular damage. Autophagy, a conserved lysosomal, self-destructive process involved in protein and organelle degradation, plays an essential role in both cellular and whole-animal homeostasis. Accumulating evidence now indicates that autophagic degradation declines with age and this gradual reduction of autophagy might have a causative role in the functional deterioration of biological systems during ageing. Indeed, loss of autophagy gene function significantly influences longevity. Moreover, genetic or pharmacological manipulations that extend lifespan in model organisms often activate autophagy. Interestingly, conserved signalling pathways and environmental factors that regulate ageing, such as the insulin/IGF-1 signalling pathway and oxidative stress response pathways converge on autophagy. In this article, we survey recent findings in invertebrates that contribute to advance our understanding of the molecular links between autophagy and the regulation of ageing. In addition, we consider related mechanisms in other organisms and discuss their similarities and idiosyncratic features in a comparative manner.

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Autophagy genes mediate the effect of calcineurin on life span inC. elegans

Cited by 56 publications

References 18 publications

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

ATG16L1 phosphorylation is oppositely regulated by CSNK2/casein kinase 2 and PPP1/protein phosphatase 1 which determines the fate of cardiomyocytes during hypoxia/reoxygenation

Autophagy and ageing: Insights from invertebrate model organisms

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