Sqstm1
M. musculus
sequestosome 1
What the model saw
Gene: Sqstm1 Organism: Mus musculus Known functions: sequestosome 1. sequestosome-1. K63-linked polyubiquitin modification-dependent protein binding. SH2 domain binding. enzyme binding. identical protein binding. ionotropic glutamate receptor binding. molecular condensate scaffold activity. molecular sequestering activity. protein binding. protein kinase C binding. protein kinase binding. protein sequestering activity. protein-containing complex binding. protein-macromolecule adaptor activity. signaling adaptor activity. signaling receptor activity. transcription coregulator activity. ubiquitin binding. ubiquitin protein ligase binding. ubiquitin-modified protein reader activity. zinc ion binding.
View unredacted entry
sequestosome 1. sequestosome-1. K63-linked polyubiquitin modification-dependent protein binding. SH2 domain binding. enzyme binding. identical protein binding. ionotropic glutamate receptor binding. molecular condensate scaffold activity. molecular sequestering activity. protein binding. protein kinase C binding. protein kinase binding. protein sequestering activity. protein-containing complex binding. protein-macromolecule adaptor activity. signaling adaptor activity. signaling receptor activity. transcription coregulator activity. ubiquitin binding. ubiquitin protein ligase binding. ubiquitin-modified protein reader activity. zinc ion binding.
Solver output
Sqstm1/p62 is a selective autophagy receptor that binds K63-linked polyubiquitinated cargo via its UBA domain and delivers substrates to the autophagosome through LC3-interacting regions, making it a central mediator of autophagic flux and proteostasis. Its molecular condensate scaffold activity enables the formation of p62 bodies that concentrate ubiquitinated proteins for autophagic degradation, directly opposing the accumulation of proteotoxic aggregates that drive aging. Additionally, p62 acts as a signaling adaptor that activates the NRF2/KEAP1 antioxidant pathway by sequestering KEAP1, thereby upregulating cytoprotective gene expression. Loss of Sqstm1 in mice leads to accumulation of ubiquitinated protein aggregates, increased oxidative stress, and accelerated aging-related pathologies, consistent with a pro-longevity role. Its protein kinase C binding and mTORC1 scaffolding activities also link it to nutrient sensing, but its dominant aging-relevant function is as an autophagy cargo receptor maintaining proteostasis.
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 Sqstm1/p62 with high confidence (0.82). The mechanistic reasoning is excellent and accurate: p62/SQSTM1 is indeed a selective autophagy receptor that binds K63-linked polyubiquitinated cargo, forms condensate bodies, activates NRF2 by sequestering KEAP1, and its loss leads to accumulation of ubiquitinated aggregates and accelerated aging pathologies. The key pathways identified (selective autophagy, NRF2-KEAP1, ubiquitin-proteasome clearance) are all well-established and relevant. The model correctly identified the mechanism class as related to macroautophagy/proteostasis. The reasoning is detailed, accurate, and well-supported by the literature.
Raw API responses
solver
{
"reasoning": "Sqstm1/p62 is a selective autophagy receptor that binds K63-linked polyubiquitinated cargo via its UBA domain and delivers substrates to the autophagosome through LC3-interacting regions, making it a central mediator of autophagic flux and proteostasis. Its molecular condensate scaffold activity enables the formation of p62 bodies that concentrate ubiquitinated proteins for autophagic degradation, directly opposing the accumulation of proteotoxic aggregates that drive aging. Additionally, p62 acts as a signaling adaptor that activates the NRF2/KEAP1 antioxidant pathway by sequestering KEAP1, thereby upregulating cytoprotective gene expression. Loss of Sqstm1 in mice leads to accumulation of ubiquitinated protein aggregates, increased oxidative stress, and accelerated aging-related pathologies, consistent with a pro-longevity role. Its protein kinase C binding and mTORC1 scaffolding activities also link it to nutrient sensing, but its dominant aging-relevant function is as an autophagy cargo receptor maintaining proteostasis.",
"confidence": 0.82,
"key_pathways": [
"selective autophagy / LC3-mediated cargo recognition",
"NRF2-KEAP1 antioxidant signaling",
"ubiquitin-proteasome and aggresome clearance"
],
"mechanism_class": "disabled_macroautophagy",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicted pro_longevity for Sqstm1/p62 with high confidence (0.82). The mechanistic reasoning is excellent and accurate: p62/SQSTM1 is indeed a selective autophagy receptor that binds K63-linked polyubiquitinated cargo, forms condensate bodies, activates NRF2 by sequestering KEAP1, and its loss leads to accumulation of ubiquitinated aggregates and accelerated aging pathologies. The key pathways identified (selective autophagy, NRF2-KEAP1, ubiquitin-proteasome clearance) are all well-established and relevant. The model correctly identified the mechanism class as related to macroautophagy/proteostasis. The reasoning is detailed, accurate, and well-supported by the literature.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 5,
"ground_truth_questionable": false
}