vhl-1
C. elegans
von Hippel-Lindau tumor suppressor homolog
What the model saw
Gene: vhl-1 Organism: Caenorhabditis elegans Known functions: von Hippel-Lindau tumor suppressor homolog. transcription corepressor activity. ubiquitin-like ligase-substrate adaptor activity.
View unredacted entry
von Hippel-Lindau tumor suppressor homolog. transcription corepressor activity. ubiquitin-like ligase-substrate adaptor activity.
Solver output
VHL-1 is the C. elegans homolog of the von Hippel-Lindau tumor suppressor, which functions as a substrate-recognition subunit of an E3 ubiquitin ligase complex (CRL2-VHL). Its primary molecular role is to target HIF-1α (HIF-1 in C. elegans) for ubiquitin-mediated proteasomal degradation under normoxic conditions, acting as a ubiquitin-like ligase-substrate adaptor. By suppressing HIF-1 transcriptional activity (consistent with its transcription corepressor annotation), VHL-1 restrains the hypoxia-inducible response. In C. elegans, loss of vhl-1 stabilizes HIF-1, which has been shown to extend lifespan under certain conditions, suggesting that VHL-1 activity normally limits HIF-1-driven longevity. However, VHL-1 also suppresses tumor-like proliferative signaling and maintains proteostasis by directing misfolded/damaged proteins to degradation, which are broadly pro-longevity functions. On balance, the dominant characterized role in C. elegans aging literature is that vhl-1 loss (HIF-1 stabilization) can extend lifespan, implying the wild-type gene is pro-longevity through restraint of aberrant HIF-1 signaling and maintenance of normal ubiquitin-proteasome flux.
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 identifies the molecular mechanism: VHL-1 targets HIF-1 for ubiquitin-mediated degradation, and loss of vhl-1 stabilizes HIF-1. However, it draws the wrong conclusion about longevity influence. The ground truth classifies vhl-1 as anti_longevity, meaning the gene normally suppresses longevity (i.e., loss of vhl-1 extends lifespan). The model actually acknowledges this in its reasoning ("vhl-1 loss (HIF-1 stabilization) can extend lifespan, implying the wild-type gene is pro-longevity") but then incorrectly labels this as "pro_longevity." If loss of vhl-1 extends lifespan, then vhl-1 is anti_longevity (it works against longevity). The model confuses the directionality: a gene whose loss extends lifespan is anti_longevity, not pro_longevity. The model's mechanistic understanding is correct but its interpretation of what "pro_longevity" vs "anti_longevity" means in this context is inverted. The confidence of 0.72 is also inappropriately high given the model's own hedging in the reasoning.
Raw API responses
solver
{
"reasoning": "VHL-1 is the C. elegans homolog of the von Hippel-Lindau tumor suppressor, which functions as a substrate-recognition subunit of an E3 ubiquitin ligase complex (CRL2-VHL). Its primary molecular role is to target HIF-1α (HIF-1 in C. elegans) for ubiquitin-mediated proteasomal degradation under normoxic conditions, acting as a ubiquitin-like ligase-substrate adaptor. By suppressing HIF-1 transcriptional activity (consistent with its transcription corepressor annotation), VHL-1 restrains the hypoxia-inducible response. In C. elegans, loss of vhl-1 stabilizes HIF-1, which has been shown to extend lifespan under certain conditions, suggesting that VHL-1 activity normally limits HIF-1-driven longevity. However, VHL-1 also suppresses tumor-like proliferative signaling and maintains proteostasis by directing misfolded/damaged proteins to degradation, which are broadly pro-longevity functions. On balance, the dominant characterized role in C. elegans aging literature is that vhl-1 loss (HIF-1 stabilization) can extend lifespan, implying the wild-type gene is pro-longevity through restraint of aberrant HIF-1 signaling and maintenance of normal ubiquitin-proteasome flux.",
"confidence": 0.72,
"key_pathways": [
"HIF-1 ubiquitin-mediated degradation (CRL2-VHL E3 ligase complex)",
"hypoxia-inducible factor signaling",
"ubiquitin-proteasome system / proteostasis"
],
"mechanism_class": "cellular_senescence",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly identifies the molecular mechanism: VHL-1 targets HIF-1 for ubiquitin-mediated degradation, and loss of vhl-1 stabilizes HIF-1. However, it draws the wrong conclusion about longevity influence. The ground truth classifies vhl-1 as anti_longevity, meaning the gene normally suppresses longevity (i.e., loss of vhl-1 extends lifespan). The model actually acknowledges this in its reasoning (\"vhl-1 loss (HIF-1 stabilization) can extend lifespan, implying the wild-type gene is pro-longevity\") but then incorrectly labels this as \"pro_longevity.\" If loss of vhl-1 extends lifespan, then vhl-1 is anti_longevity (it works against longevity). The model confuses the directionality: a gene whose loss extends lifespan is anti_longevity, not pro_longevity. The model's mechanistic understanding is correct but its interpretation of what \"pro_longevity\" vs \"anti_longevity\" means in this context is inverted. The confidence of 0.72 is also inappropriately high given the model's own hedging in the reasoning.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": true,
"reasoning_quality": 3,
"ground_truth_questionable": false
}