Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1

被引：108

作者：

Bloch, Yehudi ^{[1
,2
]}

Bouchareychas, Laura ^{[3
,4
,9
,10
]}

Merceron, Romain ^{[1
,2
]}

Skladanowska, Katarzyna ^{[1
,2
]}

Van den Bossche, Lien ^{[5
,6
]}

Detry, Sammy ^{[1
,2
]}

Govindarajan, Srinath ^{[2
,7
]}

Elewaut, Dirk ^{[2
,7
]}

Haerynck, Filomeen ^{[5
,6
,8
]}

Dullaers, Melissa ^{[5
,6
,7
]}

Adamopoulos, Iannis E. ^{[3
,4
]}

Savvides, Savvas N. ^{[1
,2
]}

机构：

[1] Univ Ghent, Dept Biochem & Microbiol, Lab Prot Biochem & Biomol Engn, B-9052 Ghent, Belgium

[2] VIB UGent Ctr Inflammat Res, B-9052 Ghent, Belgium

[3] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Dept Internal Med, Davis, CA 95616 USA

[4] Shriners Hosp Children Northern Calif, Inst Pediat Regenerat Med, Sacramento, CA 95817 USA

[5] Ghent Univ Hosp, Dept Pulm Med, Clin Immunol Res Lab, B-9000 Ghent, Belgium

[6] Ghent Univ Hosp, Jeffrey Modell Diag & Res Ctr, Ctr Primary Immunodeficiency, B-9000 Ghent, Belgium

[7] Ghent Univ Hosp, Dept Rheumatol, Lab Mol Immunol & Inflammat, B-9000 Ghent, Belgium

[8] Ghent Univ Hosp, Div Pediat Immunol & Pulmonol, Dept Pediat, B-9000 Ghent, Belgium

[9] Univ Calif San Francisco, Div Vasc & Endovasc Surg, Dept Surg, San Francisco, CA 94143 USA

[10] Vet Affairs Med Ctr, San Francisco, CA 94143 USA

来源：

IMMUNITY | 2018年 / 48卷 / 01期

关键词：

INTERLEUKIN; 23; RECEPTOR; HETERODIMERIC CYTOKINE; PROTEIN; COMPLEX; PSORIASIS; VARIANTS; CELLS; IL-12; PROMOTES; IL23R;

D O I：

10.1016/j.immuni.2017.12.008

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rb1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23: antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.

引用

页码：45 / +

页数：20

共 74 条

[1] PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution [J].