Gene Ontology annotation through association of InterPro records with GO terms

Annotation inferences using phylogenetic trees

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

PMID:11266118

Cloning of androgen-inducible gene 1 (AIG1) from human dermal papilla cells.

AIG1 was cloned as a dihydrotestosterone-inducible transcript from human dermal papilla cells, which is the origin of the gene symbol. The paper reports expression and induction only.

"We isolated a novel cDNA clone, designated as AIG1 (Androgen-inducible Gene 1), whose expression was found to be inducible by androgen."
The authors state that the function was not determined, which is why no GO biological process should rest on the androgen-induction observation.

"Further study will be needed to understand the functions of AIG1 in the androgen-regulated hair cycle."

PMID:21622095

AIG1 is a novel Pirh2-interacting protein that activates the NFAT signaling pathway.

A yeast two-hybrid screen identified AIG1 as a Pirh2-interacting protein. The remainder of the paper is an expression-biomarker study in hepatocellular carcinoma.

"Here, we identified a novel Pirh2-interacting protein, AIG1, by yeast two-hybrid screening"

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

Source of the single GO:0005515 row. IntAct records four distinct assay types for the AIG1-RCHY1 pair from this study - two hybrid, pull down, anti tag coip and confocal microscopy - rather than several sub-methods of one screen.

"Toward an understanding of the protein interaction network of the human liver."

PMID:21868574

Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen.

Imaged the paralogue ADTRP at the endothelial cell surface with TFPI and caveolin-1. This is the independent plasma-membrane evidence that AIG1 lacks, and it is why the two genes' identical GO:0005886 rows are resolved differently.

"We confirm ADTRP expression and colocalization with TFPI and caveolin-1 in ECs"

PMID:27018888

AIG1 and ADTRP are atypical integral membrane hydrolases that degrade bioactive FAHFAs.

Activity-based protein profiling identified AIG1 as a fluorophosphonate-reactive protein and established that it and ADTRP hydrolyse FAHFAs using conserved Thr and His residues.

"We show that AIG1, and the sequence-related homologous protein ADTRP, possess conserved Thr and histidine (His) residues required for FP reactivity and find that both enzymes hydrolyze the fatty-acid esters of hydroxy-fatty acid (FAHFA) class of lipids in vitro and in human cells."
Thr43 is the nucleophile. Of fifteen individual Ser/Thr-to-Ala mutants only T43A lost probe labelling entirely.

"Among the 15 individual Ser/Thr-to-Ala mutant proteins evaluated, only the T43A mutant showed a complete loss of FP-labeling"
His134 is the general base; mutating it eliminates probe labelling.

"Mutation of His134 to Ala in AIG1 (H134A) eliminated FP-labeling"
Both catalytic residues are required for the FAHFA hydrolase activity itself, not only for probe reactivity.

"The FAHFA hydrolase activities of AIG1 and ADTRP were abolished by mutating their putative catalytic nucleophilic residues Thr-43 and Thr-47, respectively"
Specificity is restricted to FAHFAs; the common phospholipid and neutral lipid classes are not substrates.

"The membrane lysates of hAIG1- and hADTRP-transfected HEK293T cells showed negligible hydrolytic activity above a mock-transfected control proteome with the majority of tested lipid substrates"
Within the FAHFA class, branching distal from the carboxylate head group is preferred.

"AIG1 and ADTRP displayed a preference for FAHFAs with branching distal from the carboxylate head group of the lipids"
shRNA knockdown in human LNCaP cells cut PAHSA hydrolysis by about 70 percent, establishing AIG1 as the principal FAHFA hydrolase of human cells.

"We next treated shAIG1 and shControl cells with 13C,2H-PAHSA and observed a ~70% reduction in hydrolysis products in the shAIG1 cells compared to shControl or uninfected cell lines"
The activity partitions to the membrane fraction of untransfected human cells, which is the localisation evidence this paper supports.

"Both KC01 and JJH260, but not THL or ABC34 also inhibited the FAHFA hydrolase activity of LNCaP cell lysates, which was mostly found in the membrane fraction"
The suggestion that catalysis occurs within the bilayer is explicitly a prediction-based inference, not a localisation or topology measurement.

"That these residues are generally predicted to be embedded within transmembrane domains of AIG1 and ADTRP indicates these enzymes could have evolved to perform hydrolytic chemistry within the cell membrane environment"

PMID:27040980

Androgen-inducible gene 1 increases the ER Ca(2+) content and cell death susceptibility against oxidative stress.

A protease-protection assay placed AIG1 in the ER membrane with five transmembrane domains, a luminal N-terminus and a cytosolic C-terminus - a different compartment and a different topology from the UniProt record.

"Analyzing the topology of AIG1 in the ER membrane using a protease-protection assay suggested"
The functional readout is also ER-based, linking AIG1 overexpression to increased ER calcium content and oxidative-stress susceptibility.

"AIG1 over-expression slightly increased susceptibility to oxidative stress, which correlated with an increased ER Ca(2+) concentration in two different cell lines."

PMID:32152231

AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice.

Elevated tissue FAHFAs are reported for Adtrp single knockouts and for AIG1/ADTRP double knockouts. The Aig1 single knockout is not reported as elevating tissue FAHFAs, so AIG1's individual in vivo contribution is not established here.

"Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs"
The specificity established in vitro holds in vivo: other lipid classes are unaffected by loss of the two enzymes.

"The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs."

PMID:38816388

Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.

Adipocyte AIG1 overexpression promotes high-fat-diet insulin resistance and pharmacological AIG1 inhibition reverses it, placing the enzyme downstream of IRF3 in a metabolic pathway.

"Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet."
The effect requires catalysis: the T43A and H134A alleles do not reproduce it, tying the metabolic phenotype to the FAHFA hydrolase activity rather than to a separate scaffolding role.

"As before, FI3KO adipocytes exhibited elevated p-AKT level and insulin-stimulated glucose uptake, which was fully suppressible by WT AIG1 overexpression, but not two different alleles of Aig1 bearing mutations in the catalytic domain (T43A and H134A)"

PMID:40303337

AIG1 protects against doxorubicin-induced cardiomyocyte ferroptosis and cardiotoxicity by promoting ubiquitination-mediated p53 degradation.

Endogenous AIG1 and Pirh2 co-immunoprecipitate from cardiomyocytes, independently corroborating the interaction behind the single GO:0005515 row.

"Co-IP results similarly indicated that endogenous AIG1 strongly interacted with Pirh2 in cardiomyocytes under steady-state conditions"
AIG1 promotes Pirh2-dependent ubiquitination of p53; removing the AIG1 region required for Pirh2 binding reduces both the Pirh2-p53 association and p53 ubiquitination.

"Importantly, the deletion of the 35-93 aa domain of AIG1 resulted in significant reductions in Pirh2-p53 interaction and p53 ubiquitination"
Degradation was measured separately from ubiquitination: a cycloheximide chase shows AIG1 silencing slows p53 turnover, so the readout is rate rather than steady-state level.

"In fact, a cycloheximide (CHX) chase assay conducted in HL-1 cardiomyocytes revealed that AIG1 silencing significantly decelerated p53 protein degradation"
A three-inhibitor panel discriminates the degradation route rather than assuming it: the AIG1-driven loss of p53 is reversed by the proteasome inhibitor MG132 but not by the autophagy or autolysosome inhibitors.

"Our results showed that protein level of p53 was reduced in response to AIG1 overexpression, an effect reversed by MG132 treatment but unaffected by 3-MA or Baf A1 under DOX stress"
The interaction was mapped by deletion of residues 35-93, a span that removes an entire transmembrane helix, so it locates a requirement rather than a contact surface.

"The results showed that Pirh2 interacted with full-length AIG1 and the AIG1 Δ161-175 aa mutant, but not with the AIG1 Δ35-93 aa mutant when co-expressed in HEK293T cells"

file:human/AIG1/AIG1-deep-research-affinage.md

Affinage mechanistic annotation for AIG1 (human)