ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism

Rasmus Pihl; Rasmus K Jensen; Emil C Poulsen; Lisbeth Jensen; Annette G Hansen; Ida B Thøgersen; József Dobó; Péter Gál; Gregers R Andersen; Jan J Enghild; Steffen Thiel

doi:10.1126/sciadv.aba7381

ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism

Rasmus Pihl, Rasmus K Jensen, Emil C Poulsen, Lisbeth Jensen, Annette G Hansen, Ida B Thøgersen, József Dobó, Péter Gál, Gregers R Andersen, Jan J Enghild, Steffen Thiel

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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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.

Original language	English
Article number	7381
Journal	Science Advances
Volume	7
Issue	2
Number of pages	17
ISSN	2375-2548
DOIs	https://doi.org/10.1126/sciadv.aba7381
Publication status	Published - Jan 2021

Keywords

ALPHA-TRYPSIN INHIBITOR
ALTERNATIVE PATHWAY
COMPLEMENT
FUNCTIONAL-ACTIVITY
HUMAN SERUM
INTER
LECTIN-PATHWAY ACTIVATION
MASP-1 NOR MASP-3
PLASMA KALLIKREIN
SEQUENCE

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title = "ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism",

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.",

keywords = "ALPHA-TRYPSIN INHIBITOR, ALTERNATIVE PATHWAY, COMPLEMENT, FUNCTIONAL-ACTIVITY, HUMAN SERUM, INTER, LECTIN-PATHWAY ACTIVATION, MASP-1 NOR MASP-3, PLASMA KALLIKREIN, SEQUENCE",

author = "Rasmus Pihl and Jensen, {Rasmus K} and Poulsen, {Emil C} and Lisbeth Jensen and Hansen, {Annette G} and Th{\o}gersen, {Ida B} and J{\'o}zsef Dob{\'o} and P{\'e}ter G{\'a}l and Andersen, {Gregers R} and Enghild, {Jan J} and Steffen Thiel",

year = "2021",

month = jan,

doi = "10.1126/sciadv.aba7381",

language = "English",

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T1 - ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism

AU - Pihl, Rasmus

AU - Jensen, Rasmus K

AU - Poulsen, Emil C

AU - Jensen, Lisbeth

AU - Hansen, Annette G

AU - Thøgersen, Ida B

AU - Dobó, József

AU - Gál, Péter

AU - Andersen, Gregers R

AU - Enghild, Jan J

AU - Thiel, Steffen

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

KW - ALPHA-TRYPSIN INHIBITOR

KW - ALTERNATIVE PATHWAY

KW - COMPLEMENT

KW - FUNCTIONAL-ACTIVITY

KW - HUMAN SERUM

KW - INTER

KW - LECTIN-PATHWAY ACTIVATION

KW - MASP-1 NOR MASP-3

KW - PLASMA KALLIKREIN

KW - SEQUENCE

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U2 - 10.1126/sciadv.aba7381

DO - 10.1126/sciadv.aba7381

M3 - Journal article

C2 - 33523981

SN - 2375-2548

VL - 7

JO - Science Advances

JF - Science Advances

IS - 2

M1 - 7381

ER -

ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism

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Keywords

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