We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress
Sign In
Advertise with Us


Thermo Fisher Scientific provides analytical instruments, lab equipment, specialty diagnostics, reagents and integrat... read more Featured Products: More products

Download Mobile App


ATTENTION: Due to the COVID-19 PANDEMIC, many events are being rescheduled for a later date, converted into virtual venues, or altogether cancelled. Please check with the event organizer or website prior to planning for any forthcoming event.
18 Mar 2021 - 21 Mar 2021
13 Apr 2021 - 16 Apr 2021

New Control Mechanism Discovered in Innate Immune System

By LabMedica International staff writers
Posted on 11 Feb 2021
Print article
Image: Inter-α-inhibitor heavy chain 4 (ITIH4) inhibits proteases in the innate immune system via novel inhibitory mechanism (Photo courtesy of Rasmus Kjeldsen Jensen, PhD).
Image: Inter-α-inhibitor heavy chain 4 (ITIH4) inhibits proteases in the innate immune system via novel inhibitory mechanism (Photo courtesy of Rasmus Kjeldsen Jensen, PhD).
Proteases are enzymes that cleave other proteins. Most often, proteases occur in cascade networks, where a particular event triggers a chain reaction in which several proteases cleave and thereby activate each other. Most well-known is probably the coagulation cascade, which causes clotting of our blood when a vessel is punctured.

Inter-α-inhibitor heavy chain 4 (ITIH4) is a liver-produced plasma protein belonging to the inter–α-inhibitor/ITIH family of proteins that consists of bikunin and six different heavy chain proteins. This protein family is also referred to as inter–α-trypsin inhibitor proteins since bikunin displays a weak inhibitory effect on proteases for which a biological role is yet to be defined.

Biomedical Scientists at Aarhus University (Aarhus, Denmark) and a colleague investigated which other proteins in the blood the so-called mannan-binding lectin–associated serine protease (MASP) proteases interact with the complement cascade. To characterize in detail how ITIH4 inhibits the MASP proteases, they isolated both free ITIH4 and ITIH4 bound to the MASP-1 protease. By the use of X-ray small-angle scattering and electron microscopy, these samples were studied. Liquid chromatography tandem-mass spectrometry was performed using a Q-Exactive plus mass spectrometer (ThermoFisher Scientific, Waltham, MA, USA).

The scientists showed 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 non-covalent, 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.

The authors concluded that the active sites of MASP within the non-covalent ITIH4-MASP complexes are catalytically competent, but downstream cleavage of C2 and C4 are inhibited by physically blocking access of the scissile bonds to the active sites. Such activity was demonstrated in human and murine serum. ITIH4 was found to be cleaved by various proteases within the protease-susceptible region (PSR), suggesting that ITIH4 is a broad-acting inhibitor that targets numerous proteases. The study was published on January 8, 2021 in the journal Science Advances.

Related Links:
Aarhus University
ThermoFisher Scientific

Gold Supplier
SARS-CoV-2/Influenza A & B/RSV Test
BIOSYNEX® AMPLIQUICK® SARS-COV-2 and Respiratory Triplex
Gold Supplier
SARS-CoV-2 Assay
COVID-19 Positive Control
STAT-NAT COVID-19 Positive Control

Print article


Molecular Diagnostics

view channel
Image: Histopathologic image from a patient with Li Fraumeni syndrome showing accumulation of mutant TP53 in tumoral cells (Photo courtesy of Thierry Soussi, PhD).

Clinical Germline Testing Evaluated for Pediatric Cancer Patients

Pediatric cancer is rare, with fewer than 10,000 solid tumors diagnosed in children annually in the USA. Previous studies interrogating germline predisposition broadly across pediatric cancer types have... Read more


view channel

Mindray and Tencent AI Lab to Jointly Develop AI Products for Blood Disease Screening and In Vitro Diagnosis

Shenzhen Mindray Biomedical Electronics Co., Ltd. (Shenzhen, China) has signed an AI cooperation framework agreement with Tencent AI Lab (Shenzhen, China) to jointly develop AI products for blood cell... Read more
Copyright © 2000-2021 Globetech Media. All rights reserved.