Progranulin-Derived Atsttrin Directly Binds to TNFRSF25 (DR3) and Inhibits TNF-Like Ligand 1A (TL1A) Activity

Cui Liu,De-Shan Liu,Xing-Xia Li,Wen Liu,Wei Gao,Bernhard Ryffel

doi:10.1371/journal.pone.0092743

Cui Liu, De-Shan Liu + Show 4 more

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https://doi.org/10.1371/journal.pone.0092743

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Abstract

Atsttrin, a progranulin (PGRN)-derived molecule composed of three TNFR-binding domains of PGRN, binds to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we screened the associations of Atsttrin and other members in TNFR subfamily, which led to the discovery of TNFRSF25 (DR3) as an additional Atsttrin-interacting member in TNFR family. Similar to TNFR1 and TNFR2, DR3 also directly bound to Atsttrin. The first three cysteine-rich domains (CRD) in the extracellular portion of DR3 were required for this interaction. Atsttrin inhibited the interaction between DR3 and its TNF-Like Ligand 1A (TL1A). In addition, Atsttrin inhibited TL1A-stimulated target gene expressions and neutralized TL1A-enhanced osteoclastogenesis in vitro. Furthermore, Atsttrin ameliorated the pathology in dextran sulfate sodium induced colitis. Taken together, these findings not only provide the new insights into Atsttrin's therapeutic action in inflammatory arthritis, but may also present Atsttrin as a novel biological agent for treating various types of diseases associated with TL1A/DR3 pathway.

Highlights

Progranulin (PGRN) is a growth factor with multiple biological functions including anti-inflammation and immune regulations [1]
The previous finding that Atsttrin bound to TNFR1 and TNFR2 [3], and the recent report that PGRN bound to the 2nd and 3rd cysteine rich domain (CRD) of the extracellular portion of TNF receptors (TNFR) [26], promoted us to determine whether Atsttrin associated with other members in TNFR superfamily
We cloned the extracellular portions of all 28 TNFR super family members which have cysteine-rich domains (CRD) in their extracellular potion, with the exception of Fn14, and tested their interaction with Atsttrin which was cloned into another yeast expression plasmid, using yeast two-hybrid system

Summary

Introduction

Progranulin (PGRN) is a growth factor with multiple biological functions including anti-inflammation and immune regulations [1]. PGRN was reported to bind to TNF receptors (TNFR) through three individual and separate binding domains involving granulin A, C and F plus adjacent linkers [3]. Atsttrin (Antagonist of TNF/TNFR Signaling via Targeting to TNF Receptors) is an engineered molecule composed of half units of granulins A, C and F plus linkers P3, P4 and P5 that appears to be the ‘‘minimal’’ engineered molecule retaining affinity to TNFR [3,4,5]. Recombinant Atsttrin protein effectively attenuated inflammation in several animal models, including collagen antibody- and collagen-induced arthritis models, TNF transgenic mice and dermatitis model [3,6], indicating that Atsttrin may represent a novel biologics for treating various kinds of TNF/TNFR associated inflammatory diseases and conditions [3,4,5,7]

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