ISC1
S. cerevisiae
inositol phosphosphingolipid phospholipase
What the model saw
Gene: ISC1 Organism: Saccharomyces cerevisiae Known functions: inositol phosphosphingolipid phospholipase. catalytic activity. inositol phosphosphingolipid phospholipase activity. sphingomyelin phosphodiesterase activity. sphingophospholipase activity.
View unredacted entry
inositol phosphosphingolipid phospholipase. catalytic activity. inositol phosphosphingolipid phospholipase activity. sphingomyelin phosphodiesterase activity. sphingophospholipase activity.
Solver output
ISC1 encodes an inositol phosphosphingolipid phospholipase C (a neutral sphingomyelinase homolog) that hydrolyzes complex sphingolipids to generate ceramide in yeast. Ceramide produced by ISC1 acts as a bioactive lipid second messenger that modulates the TORC1/PP2A signaling axis; specifically, ISC1-derived ceramide activates the protein phosphatase 2A (PP2A) complex containing Sit4, which in turn downregulates TORC1 activity and promotes stress resistance and longevity. Loss of ISC1 in yeast leads to shortened chronological and replicative lifespan, increased mitochondrial dysfunction, and impaired retrograde signaling, consistent with a pro-longevity role. The ceramide-PP2A-TORC1 axis places ISC1 squarely within the deregulated nutrient-sensing hallmark of aging, as ceramide signaling modulates nutrient-responsive kinase cascades analogous to dietary restriction pathways.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model correctly predicted ISC1 as pro_longevity with high-quality mechanistic reasoning. It accurately described ISC1's role as an inositol phosphosphingolipid phospholipase C that generates ceramide, which activates PP2A/Sit4 to downregulate TORC1, promoting longevity. The model also correctly noted that ISC1 deletion leads to shortened chronological and replicative lifespan, mitochondrial dysfunction, and impaired retrograde signaling. The mechanism class of deregulated_nutrient_sensing is appropriate given the ceramide-PP2A-TORC1 axis. The confidence of 0.65 is reasonable. Overall, this is an excellent prediction with accurate and detailed mechanistic reasoning.
Raw API responses
solver
{
"reasoning": "ISC1 encodes an inositol phosphosphingolipid phospholipase C (a neutral sphingomyelinase homolog) that hydrolyzes complex sphingolipids to generate ceramide in yeast. Ceramide produced by ISC1 acts as a bioactive lipid second messenger that modulates the TORC1/PP2A signaling axis; specifically, ISC1-derived ceramide activates the protein phosphatase 2A (PP2A) complex containing Sit4, which in turn downregulates TORC1 activity and promotes stress resistance and longevity. Loss of ISC1 in yeast leads to shortened chronological and replicative lifespan, increased mitochondrial dysfunction, and impaired retrograde signaling, consistent with a pro-longevity role. The ceramide-PP2A-TORC1 axis places ISC1 squarely within the deregulated nutrient-sensing hallmark of aging, as ceramide signaling modulates nutrient-responsive kinase cascades analogous to dietary restriction pathways.",
"confidence": 0.65,
"key_pathways": [
"ceramide-PP2A-TORC1 signaling",
"sphingolipid metabolism",
"retrograde mitochondrial signaling"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicted ISC1 as pro_longevity with high-quality mechanistic reasoning. It accurately described ISC1's role as an inositol phosphosphingolipid phospholipase C that generates ceramide, which activates PP2A/Sit4 to downregulate TORC1, promoting longevity. The model also correctly noted that ISC1 deletion leads to shortened chronological and replicative lifespan, mitochondrial dysfunction, and impaired retrograde signaling. The mechanism class of deregulated_nutrient_sensing is appropriate given the ceramide-PP2A-TORC1 axis. The confidence of 0.65 is reasonable. Overall, this is an excellent prediction with accurate and detailed mechanistic reasoning.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 5,
"ground_truth_questionable": false
}