Heparan sulphate binding controls in vivo half-life of the HpARI protein family

TY - JOUR

T1 - Heparan sulphate binding controls in vivo half-life of the HpARI protein family

AU - Colomb, Florent

AU - Jamwal, Abhishek

AU - Ogunkanbi, Adefunke

AU - Frangova, Tanya

AU - Savage, Alice R.

AU - Kelly, Sarah

AU - Wright, Gavin J.

AU - Higgins, Matthew K.

AU - McSorley, Henry J.

N1 - Copyright: © 2024, Colomb et al.

PY - 2024/11/8

Y1 - 2024/11/8

N2 - The parasitic nematode Heligmosomoides polygyrus bakeri secretes the HpARI family, which bind to IL-33, either suppressing (HpARI1 and HpARI2) or enhancing (HpARI3) responses to the cytokine. We previously showed that HpARI2 also bound to DNA via its first complement control protein (CCP1) domain. Here, we find that HpARI1 can also bind DNA, while HpARI3 cannot. Through the production of HpARI2/HpARI3 CCP1 domain-swapped chimeras, DNA-binding ability can be transferred, and correlates with in vivo half-life of administered proteins. We found that HpARI1 and HpARI2 (but not HpARI3) also binds to the extracellular matrix component heparan sulphate (HS), and structural modelling showed a basic charged patch in the CCP1 domain of HpARI1 and HpARI2 (but not HpARI3) which could facilitate these interactions. Finally, a mutant of HpARI2 was produced which lacked DNA and HS binding, and was also shown to have a short half-life in vivo. Therefore, we propose that during infection the suppressive HpARI1 and HpARI2 proteins have long-lasting effects at the site of deposition due to DNA and/or extracellular matrix interactions, while HpARI3 has a shorter half-life due to a lack of these interactions.

AB - The parasitic nematode Heligmosomoides polygyrus bakeri secretes the HpARI family, which bind to IL-33, either suppressing (HpARI1 and HpARI2) or enhancing (HpARI3) responses to the cytokine. We previously showed that HpARI2 also bound to DNA via its first complement control protein (CCP1) domain. Here, we find that HpARI1 can also bind DNA, while HpARI3 cannot. Through the production of HpARI2/HpARI3 CCP1 domain-swapped chimeras, DNA-binding ability can be transferred, and correlates with in vivo half-life of administered proteins. We found that HpARI1 and HpARI2 (but not HpARI3) also binds to the extracellular matrix component heparan sulphate (HS), and structural modelling showed a basic charged patch in the CCP1 domain of HpARI1 and HpARI2 (but not HpARI3) which could facilitate these interactions. Finally, a mutant of HpARI2 was produced which lacked DNA and HS binding, and was also shown to have a short half-life in vivo. Therefore, we propose that during infection the suppressive HpARI1 and HpARI2 proteins have long-lasting effects at the site of deposition due to DNA and/or extracellular matrix interactions, while HpARI3 has a shorter half-life due to a lack of these interactions.

KW - Heligmosoides polygyrus bakeri

KW - IL-33

KW - heparan sulphate

KW - immunology

KW - infectious disease

KW - inflammation

KW - microbiology

KW - mouse

UR - https://www.scopus.com/pages/publications/85209170885

U2 - 10.7554/eLife.99000

DO - 10.7554/eLife.99000

M3 - Article

C2 - 39514278

SN - 2050-084X

VL - 13

JO - eLife

JF - eLife

M1 - RP99000

ER -