ArticleScience advances2021
ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism.
Article in Science advances, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
38 citing papers in PubMed, 56 citations in OpenAlex.
- Neonatal hyperoxia promotes macrophage senescence and lung injury via a p38MAPK-dependent secretome.American journal of respiratory cell and molecular biology · 2026Article
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- Role of ITIH4 in Modulating YAP/TAZ-Mediated Apoptosis of Type II Alveolar Epithelium during Acute Respiratory Distress Syndrome.Pharmaceutical research · 2026Article
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- Serum complement system activation in normal healing and atrophic non-union of human long bone fractures.Frontiers in immunology · 2026Article
- A Comprehensive Analysis of the ITIH Family Across Multiple Cancer Types and an Initial Investigation of ITIH1 in Gastric Cancer.Current medicinal chemistry · 2026Article
- Proteomic signatures of COVID-19 Post-Vaccination/Post-Infection Syndrome (PV/PIS): insights into immune dysregulation and coagulopathy.Frontiers in cellular and infection microbiology · 2026Article
- Proteolytic profiling of human plasma reveals an immunoactive complement C3 fragment.The EMBO journal · 2025Article
- Long-read sequencing reveals the RNA isoform repertoire of neuropsychiatric risk genes in human brain.Genome biology · 2025Article
- Particulate matter-related ITIH4 deficiency is associated with an emphysema phenotype of COPD through JNK-dependent and JNK-independent signalling.The European respiratory journal · 2025Article
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- Revealing the Oxidative Stress-Related Molecular Characteristics and Potential Therapeutic Targets of Schizophrenia through Integrated Gene Expression Data Analysis.Molecular neurobiology · 2025Article
- Article
- Identification of noval diagnostic biomarker for HFpEF based on proteomics and machine learning.Proteome science · 2025Article
- Developing a genome-wide long sequence-specific tag for sex identification in spotted knifejaw (Oplegnathus punctatus).Molecular genetics and genomics : MGG · 2025Article
- Increased levels of ficolin-1 and of C3dg are independently associated with high risk of infection in patients with chronic kidney disease: a prospective cohort study.Frontiers in immunology · 2025Article
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- Development of DNA Insertion-specific Markers Based on the Intron Region of Oplegnathus punctatus itih4b for Genetic Sex Identification.Marine biotechnology (New York, N.Y.) · 2024Article
- Infectious parvovirus B19 circulates in the blood coated with active host protease inhibitors.Nature communications · 2024Article
- Unraveling the impact of different liposomal formulations on the plasma protein corona composition might give hints on the targeting capability of nanoparticles.Nanoscale advances · 2024Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inter-α-inhibitor heavy chain 4 (ITIH4) is a poorly characterized plasma protein that is proteolytically processed in multiple pathological conditions. However, no biological function of ITIH4 has been identified. Here, we show that ITIH4 is cleaved by several human proteases within a protease-susceptible region, enabling ITIH4 to function as a protease inhibitor. This is exemplified by its inhibition of mannan-binding lectin-associated serine protease-1 (MASP-1), MASP-2, and plasma kallikrein, which are key proteases for intravascular host defense. 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. ITIH4 inhibits the MASPs by sterically preventing larger protein substrates from accessing their active sites, which remain accessible and fully functional toward small substrates. Thus, we demonstrate that ITIH4 functions as a protease inhibitor by a previously undescribed inhibitory mechanism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.