Genetic analysis of hyl-1, the C. elegans homolog of LAG1/LASS1

Tedesco, Patricia M.; Jiang, James J.; Wang, Jinqing; Jazwinski, S. Michal; Johnson, Thomas E.

doi:10.1007/s11357-008-9046-3

Cited by 23 publications

(23 citation statements)

References 36 publications

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“…HYL-2 synthesizes a ceramide homolog that has a pro-survival effect, while the ceramide generated by Lag1 homolog HYL-1 has an apoptotic effect 103 . This is consistent with the lifespan extension seen in the roundworm on knockdown of hyl-1 105 .…”

Section: Retrograde Response In Other Organismssupporting

confidence: 88%

The Retrograde Response

Jazwinski

2014

Progress in Molecular Biology and Translational Science

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The retrograde response was discovered in Saccharomyces cerevisiae as a signaling pathway from the mitochondrion to the nucleus that triggers an array of gene regulatory changes in the latter. The activation of the retrograde response compensates for the deficits associated with aging, and thus it extends yeast replicative lifespan. The retrograde response is activated by the progressive decline in mitochondrial membrane potential during aging that is the result of increasing mitochondrial dysfunction. The ensuing metabolic adaptations and stress resistance can only delay the inevitable demise of the yeast cell. The retrograde response is embedded in a network of signal transduction pathways that impinge upon virtually every aspect of cell physiology. Thus, its manifestations are complicated. Many of these pathways have been implicated in lifespan regulation quite independently of the retrograde response. Together, they operate in a delicate balance in promoting longevity. The retrograde response is closely aligned with cell quality control, often performing when quality control is not sufficient to assure longevity. Among the key pathways related to this aspect of retrograde signaling are target of rapamycin (TOR) and ceramide signaling. The retrograde response can also be found in other organisms, including Caenorhabditis elegans, Drosophila melanogaster, mouse, and human, where it exhibits an ever increasing complexity that may be corralled by the transcription factor NFκB. The retrograde response may have evolved as a cytoprotective mechanism that senses and defends the organism from pathogens and environmental toxins.

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Section: Retrograde Response In Other Organismssupporting

confidence: 88%

The Retrograde Response

Jazwinski

2014

Progress in Molecular Biology and Translational Science

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“…Several studies reported that no single deletion of any of the three C. elegans CerS genes resulted in life span extension (Deng et al, 2008, Tedesco et al, 2008, Menuz et al, 2009), but rather deletion of hyl-2 reduced life span slightly (Mosbech et al, 2013). By switching to an RNAi feeding approach, however, to target the Lag1p motif in hyl-1, Tedesco and coworkers observed a small (about 15%) but reproducible increase in longevity (Tedesco et al, 2008). It is notable that the longevity effect of hyl-1 RNAi is accompanied by significant reduction of mRNA levels of both hyl-1 and hyl-2, so it was possible that both hyl-1 and hyl-2 functions were reduced by targeting the shared Lag1p motif after RNAi.…”

Section: Elegans Serine Palmitoyltransferase (Spt)mentioning

confidence: 99%

Caenorhabditis elegans as a model to study sphingolipid signaling

Deng

Kolesnick

2015

Biological Chemistry

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Sphingolipid signaling in Caenorhabditis elegans is vital for sensing environmental change and effecting appropriate cellular response. Many molecular components in sphingolipid intermediary metabolism are conserved throughout evolution. Here we review use of C. elegans as a model system for conducting sphingolipid-based scientific investigation, which has helped us better understand vital roles these remarkable lipids play in human metabolism and disease.

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“…In C. elegans the sphingolipids are of less structural complexity as the sphingoid long chain base exclusively constitutes a C17 iso - or anteiso -branched chain as illustrated in Figure S1. C. elegans comprises three ceramide synthases HYL-1, HYL-2, and LAGR-1, each containing a Lag1p motif required for ceramide synthase activity [6], [7]. It has been shown that radiation-induced apoptosis in the germ line is inhibited in hyl-1(ok976) , lagr-1(gk327/gk331) , and hyl-1(ok976);lagr-1(gk327) animals, which can be relieved by injection of C16 ceramide [8].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, hyl-2(gnv1) animals contain less C20-22 ceramides and sphingomyelins but more with C24-26. Tedesco et al [7] recently showed that RNAi targeted against the Lag1p motif in hyl-1 extended lifespan and reduced mRNA levels of both hyl-1 and hyl-2 , while hyl-1 deletion mutants ( hyl-1(ok976/gk203)) showed no alterations in lifespan and an increased level of hyl-2 mRNA.…”

Section: Introductionmentioning

confidence: 99%

Functional Loss of Two Ceramide Synthases Elicits Autophagy-Dependent Lifespan Extension in C. elegans

et al. 2013

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Ceramide and its metabolites constitute a diverse group of lipids, which play important roles as structural entities of biological membranes as well as regulators of cellular growth, differentiation, and development. The C. elegans genome comprises three ceramide synthase genes; hyl-1, hyl-2, and lagr-1. HYL-1 function is required for synthesis of ceramides and sphingolipids containing very long acyl-chains (≥C24), while HYL-2 is required for synthesis of ceramides and sphingolipids containing shorter acyl-chains (≤C22). Here we show that functional loss of HYL-2 decreases lifespan, while loss of HYL-1 or LAGR-1 does not affect lifespan. We show that loss of HYL-1 and LAGR-1 functions extend lifespan in an autophagy-dependent manner, as knock down of the autophagy-associated gene ATG-12 abolishes hyl-1;lagr-1 longevity. The transcription factors PHA-4/FOXA, DAF-16/FOXO, and SKN-1 are also required for the observed lifespan extension, as well as the increased number of autophagosomes in hyl-1;lagr-1 animals. Both autophagic events and the transcription factors PHA-4/FOXA, DAF-16, and SKN-1 have previously been associated with dietary restriction-induced longevity. Accordingly, we find that hyl-1;lagr-1 animals display reduced feeding, increased resistance to heat, and reduced reproduction. Collectively, our data suggest that specific sphingolipids produced by different ceramide synthases have opposing roles in determination of C. elegans lifespan. We propose that loss of HYL-1 and LAGR-1 result in dietary restriction-induced autophagy and consequently prolonged longevity.

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Genetic analysis of hyl-1, the C. elegans homolog of LAG1/LASS1

Cited by 23 publications

References 36 publications

The Retrograde Response

The Retrograde Response

Caenorhabditis elegans as a model to study sphingolipid signaling

Functional Loss of Two Ceramide Synthases Elicits Autophagy-Dependent Lifespan Extension in C. elegans

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