ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism

作者：Rasmus Pihl, R. K. Jensen, E. Poulsen, Lisbeth Jensen, A. Hansen, I. Thøgersen, J. Dobó, P. Gál, G. Andersen, J. Enghild, S. Thiel · 发表于：Science Advances · 年份：2021 · DOI：10.1126/sciadv.aba7381 · 被引用次数：54 · 研究领域：Medicine

ITIH4 forms complexes with proteases upon cleavage that inhibit proteolysis by a novel inhibitory mechanism. 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.