Gene Ontology annotation through association of InterPro records with GO terms
Combined Automated Annotation using Multiple IEA Methods
ITIH4 serum concentration increases during acute-phase processes in human patients and is up-regulated by interleukin-6 in hepatocarcinoma HepG2 cells.
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ITIH4 serum concentration rises during several human acute-phase conditions.
"The serum concentration of the inter-alpha trypsin inhibitor heavy chain 4 protein (ITIH4) increases (from 1.4-3 times)"
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IL-6 induces ITIH4 expression and secretion in HepG2 cells.
"HepG2 cell line we have observed up-regulation of ITIH4 mRNA expression upon dose-response treatments with interleukin-6 (IL-6)"
The human plasma proteome: a nonredundant list developed by combination of four separate sources.
BIP co-chaperone MTJ1/ERDJ1 interacts with inter-alpha-trypsin inhibitor heavy chain 4.
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DNAJC1/HTJ1 SANT2 binds the C-terminal third of ITIH4.
"SANT2 binds to a carboxyl-terminal fragment that corresponds to the last third of the new ITIH4 isoform sequence"
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The proteins co-immunoprecipitate from liver, and SANT2 protects an ITIH4 fragment from kallikrein processing in vitro.
"ITIH4 and MTJ1 co-immunoprecipitate from total liver protein extracts and SANT2 protects the ITIH4(588-930) recombinant fragment from being processed by kallikrein in vitro"
Inter-alpha-trypsin inhibitor heavy chain 4 is a novel marker of acute ischemic stroke.
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Circulating ITIH4 was depleted in acute ischemic stroke and returned toward normal during recovery.
"The ITIH4 protein was completely absent in AIS patients as compared to those in the control group, and serum levels returned to normal in AIS patients as their condition improved"
Human inter-alpha-trypsin inhibitor heavy chain H3 gene. Genomic organization, promoter analysis, and gene linkage.
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The paper studies ITIH3 gene organization and regulation, not ITIH4 inhibitor activity.
"To understand more about the human inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) expression"
Large-scale proteomics and phosphoproteomics of urinary exosomes.
Proteomic analysis of microvesicles from plasma of healthy donors reveals high individual variability.
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
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Approximately 900 proteins were detected in pooled EPS-urine exosome preparations.
"In pooled EPS-urine exosome samples, ~900 proteins were detected."
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The authors caution that proteins in the preparation can also be soluble.
"some of these proteins could also exist as a soluble form"
Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver.
Characterization of the Extracellular Matrix of Normal and Diseased Tissues Using Proteomics.
Exocytosis of platelet dense granule content
ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism.
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Cleavage enables ITIH4 to inhibit multiple human serine proteases.
"Here, we show that ITIH4 is cleaved by several human proteases within a protease-susceptible region, enabling ITIH4 to function as a protease inhibitor."
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ITIH4 forms noncovalent inhibitory complexes with MASP-1, MASP-2, and plasma kallikrein through its VWA domain.
"Mechanistically, ITIH4 acts as bait that, upon cleavage, forms a noncovalent, inhibitory complex with the executing protease that depends on the ITIH4 von Willebrand factor A domain."
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ITIH4 directly inhibits lectin-pathway complement activation.
"ITIH4 efficiently and dose-dependently inhibited C4 and C3 deposition"
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ITIH4 is not incorporated into bikunin-linked proteoglycan complexes.
"ITIH4 lacks a C-terminal consensus sequence, which is present in all other ITIHs, that is required for the formation of bikunin-ITIH complexes."
Purification and characterization of a novel glycoprotein which has significant homology to heavy chains of inter-alpha-trypsin inhibitor family from human plasma.
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Purified plasma ITIH4 is not a bikunin-containing complex.
"Since GP120 showed no bikunin sequence, and chondroitinase treatment and alkaline treatment of GP120 did not affect its molecular weight, we concluded that GP120 was not a complex with bikunin."
Cloning and characterization of cDNA for inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP), a novel human plasma glycoprotein.
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ITIH4 is a secreted liver-derived 930-amino-acid protein.
"The N-terminal 28 residues corresponded to a signal peptide for secretion."
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ITIH4 has a distinctive C-terminal region not homologous to other ITIH heavy chains.
"the C-terminal 300 residues showed no homology with the heavy chains"
Purification and characterization of a novel substrate for plasma kallikrein (PK-120) in human plasma.
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ITIH4/PK-120 was directly purified from plasma as a kallikrein-sensitive single-chain glycoprotein.
"A 120 kDa plasma protein, which is susceptible to plasma kallikrein, was purified from human plasma"
UniProtKB record for human ITIH4 (Q14624)
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ITIH4 is a reviewed 930-amino-acid secreted precursor.
"Reviewed; 930 AA."
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UniProt assigns an N-terminal signal peptide.
"FT SIGNAL 1..28"
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UniProt assigns a VWA domain.
"FT DOMAIN 272..432"
Manual literature and annotation review notes for human ITIH4
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ITIH4 directly inhibits intravascular serine proteases but does not participate in bikunin-linked hyaluronan complexes.
"The strongest direct evidence is PMID:33523981."
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All 15 GOA annotation groups were manually adjudicated.
"## Annotation decisions"
Manual literature synthesis for human ITIH4 (Q14624)
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ITIH4 is an extracellular bait-and-trap serine-protease inhibitor distinct from bikunin-linked ITIH heavy chains.
"The core demonstrated molecular function is extracellular serine-type endopeptidase inhibition."