Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator of MASP-2

Dávid Héja, Andrea Kocsis, J. Dobó, Katalin Szilágyi, Róbert Szász, P. Závodszky, G. Pál, P. Gál

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

The lectin pathway of complement activation is an important component of the innate immune defense. The initiation complexes of the lectin pathway consist of a recognition molecule and associated serine proteases. Until now the autoactivating mannose-binding lectin-associated serine protease (MASP)-2 has been considered the autonomous initiator of the proteolytic cascade. The role of themuch more abundant MASP-1 protease was controversial. Using unique, monospecific inhibitors against MASP-1 and MASP-2, we corrected themechanism of lectin-pathway activation. In normal human serum, MASP-2 activation strictly depends on MASP-1. MASP-1 activates MASP-2 and,moreover, inhibition of MASP-1 prevents autoactivation of MASP-2. Furthermore we demonstrated that MASP-1 produces 60% of C2a responsible for C3 convertase formation.

Original languageEnglish
Pages (from-to)10498-10503
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number26
DOIs
Publication statusPublished - Jun 26 2012

Fingerprint

Mannose-Binding Lectin Complement Pathway
Mannose-Binding Lectin
Serine Proteases
Lectins
Complement C3-C5 Convertases
Complement Activation

Keywords

  • Canonical inhibitor
  • Complement system
  • Directed evolution
  • Innate immunity
  • Phage display

ASJC Scopus subject areas

  • General

Cite this

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title = "Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator of MASP-2",
abstract = "The lectin pathway of complement activation is an important component of the innate immune defense. The initiation complexes of the lectin pathway consist of a recognition molecule and associated serine proteases. Until now the autoactivating mannose-binding lectin-associated serine protease (MASP)-2 has been considered the autonomous initiator of the proteolytic cascade. The role of themuch more abundant MASP-1 protease was controversial. Using unique, monospecific inhibitors against MASP-1 and MASP-2, we corrected themechanism of lectin-pathway activation. In normal human serum, MASP-2 activation strictly depends on MASP-1. MASP-1 activates MASP-2 and,moreover, inhibition of MASP-1 prevents autoactivation of MASP-2. Furthermore we demonstrated that MASP-1 produces 60{\%} of C2a responsible for C3 convertase formation.",
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author = "D{\'a}vid H{\'e}ja and Andrea Kocsis and J. Dob{\'o} and Katalin Szil{\'a}gyi and R{\'o}bert Sz{\'a}sz and P. Z{\'a}vodszky and G. P{\'a}l and P. G{\'a}l",
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T1 - Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator of MASP-2

AU - Héja, Dávid

AU - Kocsis, Andrea

AU - Dobó, J.

AU - Szilágyi, Katalin

AU - Szász, Róbert

AU - Závodszky, P.

AU - Pál, G.

AU - Gál, P.

PY - 2012/6/26

Y1 - 2012/6/26

N2 - The lectin pathway of complement activation is an important component of the innate immune defense. The initiation complexes of the lectin pathway consist of a recognition molecule and associated serine proteases. Until now the autoactivating mannose-binding lectin-associated serine protease (MASP)-2 has been considered the autonomous initiator of the proteolytic cascade. The role of themuch more abundant MASP-1 protease was controversial. Using unique, monospecific inhibitors against MASP-1 and MASP-2, we corrected themechanism of lectin-pathway activation. In normal human serum, MASP-2 activation strictly depends on MASP-1. MASP-1 activates MASP-2 and,moreover, inhibition of MASP-1 prevents autoactivation of MASP-2. Furthermore we demonstrated that MASP-1 produces 60% of C2a responsible for C3 convertase formation.

AB - The lectin pathway of complement activation is an important component of the innate immune defense. The initiation complexes of the lectin pathway consist of a recognition molecule and associated serine proteases. Until now the autoactivating mannose-binding lectin-associated serine protease (MASP)-2 has been considered the autonomous initiator of the proteolytic cascade. The role of themuch more abundant MASP-1 protease was controversial. Using unique, monospecific inhibitors against MASP-1 and MASP-2, we corrected themechanism of lectin-pathway activation. In normal human serum, MASP-2 activation strictly depends on MASP-1. MASP-1 activates MASP-2 and,moreover, inhibition of MASP-1 prevents autoactivation of MASP-2. Furthermore we demonstrated that MASP-1 produces 60% of C2a responsible for C3 convertase formation.

KW - Canonical inhibitor

KW - Complement system

KW - Directed evolution

KW - Innate immunity

KW - Phage display

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U2 - 10.1073/pnas.1202588109

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M3 - Article

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