vps-36
C. elegans
Vacuolar protein-sorting-associated protein 36
What the model saw
Gene: vps-36 Organism: Caenorhabditis elegans Known functions: Vacuolar protein-sorting-associated protein 36. phosphatidylinositol-3-phosphate binding. ubiquitin binding.
View unredacted entry
Vacuolar protein-sorting-associated protein 36. phosphatidylinositol-3-phosphate binding. ubiquitin binding.
Solver output
VPS-36 is a core component of the ESCRT-II complex, which recognizes ubiquitinated cargo via its ubiquitin-binding domain and binds phosphatidylinositol-3-phosphate (PI3P) on endosomal membranes to facilitate multivesicular body (MVB) biogenesis. Proper MVB/endolysosomal sorting is essential for degradation of ubiquitinated proteins and damaged receptors, directly supporting proteostasis. Loss of ESCRT function impairs lysosomal degradation pathways that overlap with autophagy flux, leading to accumulation of proteotoxic cargo. In C. elegans, endosomal sorting and lysosomal function are tightly linked to lifespan extension pathways, including those downstream of reduced insulin/IGF-1 signaling. Thus, the normal function of vps-36 in maintaining endolysosomal proteostasis is expected to be pro-longevity.
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 pro_longevity for vps-36. The mechanistic reasoning is sound and well-grounded: VPS-36 as an ESCRT-II component involved in MVB biogenesis, ubiquitinated cargo sorting, and endolysosomal proteostasis is a reasonable explanation for why loss of this gene would be detrimental to lifespan. The model correctly identifies the PI3P binding and ubiquitin binding functions from the entry and connects them to proteostasis maintenance. The mechanism class "disabled_macroautophagy" is slightly imprecise (ESCRT/MVB pathway is more endosomal sorting than macroautophagy per se), but the overall mechanistic narrative is coherent and largely correct. Confidence of 0.65 is appropriately calibrated given the indirect evidence.
Raw API responses
solver
{
"reasoning": "VPS-36 is a core component of the ESCRT-II complex, which recognizes ubiquitinated cargo via its ubiquitin-binding domain and binds phosphatidylinositol-3-phosphate (PI3P) on endosomal membranes to facilitate multivesicular body (MVB) biogenesis. Proper MVB/endolysosomal sorting is essential for degradation of ubiquitinated proteins and damaged receptors, directly supporting proteostasis. Loss of ESCRT function impairs lysosomal degradation pathways that overlap with autophagy flux, leading to accumulation of proteotoxic cargo. In C. elegans, endosomal sorting and lysosomal function are tightly linked to lifespan extension pathways, including those downstream of reduced insulin/IGF-1 signaling. Thus, the normal function of vps-36 in maintaining endolysosomal proteostasis is expected to be pro-longevity.",
"confidence": 0.65,
"key_pathways": [
"ESCRT-II/multivesicular body (MVB) biogenesis",
"endolysosomal proteostasis and ubiquitinated cargo degradation",
"PI3P-mediated endosomal sorting"
],
"mechanism_class": "disabled_macroautophagy",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicted pro_longevity for vps-36. The mechanistic reasoning is sound and well-grounded: VPS-36 as an ESCRT-II component involved in MVB biogenesis, ubiquitinated cargo sorting, and endolysosomal proteostasis is a reasonable explanation for why loss of this gene would be detrimental to lifespan. The model correctly identifies the PI3P binding and ubiquitin binding functions from the entry and connects them to proteostasis maintenance. The mechanism class \"disabled_macroautophagy\" is slightly imprecise (ESCRT/MVB pathway is more endosomal sorting than macroautophagy per se), but the overall mechanistic narrative is coherent and largely correct. Confidence of 0.65 is appropriately calibrated given the indirect evidence.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 4,
"ground_truth_questionable": false
}