β-arrestin 2 quenches TLR signaling to facilitate the immune evasion of EPEC

Zijuan Chen, Ruixue Zhou, Yihua Zhang, Doudou Hao, Yu Wang, Shichao Huang, Ningning Liu, Chunmei Xia, Nissan Yissachar, Feng Huang, Yiwei Chu, Dapeng Yan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The protein translocated intimin receptor (Tir) from enteropathogenic Escherichia coli shares sequence similarity with the host cellular immunoreceptor tyrosine-based inhibition motifs (ITIMs). The ITIMs of Tir are required for Tir-mediated immune inhibition and evasion of host immune responses. However, the underlying molecular mechanism by which Tir regulates immune inhibition remains unclear. Here we demonstrated that β-arrestin 2, which is involved in the G-protein-coupled receptor (GPCR) signal pathway, interacted with Tir in an ITIM-dependent manner. For the molecular mechanism, we found that β-arrestin 2 enhanced the recruitment of SHP-1 to Tir. The recruited SHP-1 inhibited K63-linked ubiquitination of TRAF6 by dephosphorylating TRAF6 at Tyr288, and inhibited K63-linked ubiquitination and phosphorylation of TAK1 by dephosphorylating TAK1 at Tyr206, which cut off the downstream signal transduction and subsequent cytokine production. Moreover, the inhibitory effect of Tir on immune responses was diminished in β-arrestin 2-deficient mice and macrophages. These findings suggest that β-arrestin 2 is a key regulator in Tir-mediated immune evasion, which could serve as a new therapeutic target for bacterial infectious diseases.

Original languageEnglish
Pages (from-to)1423-1437
Number of pages15
JournalGut Microbes
Volume11
Issue number5
DOIs
StatePublished - 2 Sep 2020

Bibliographical note

Publisher Copyright:
© 2020, © 2020 Taylor & Francis Group, LLC.

Funding

This work was supported by the National Natural Science Foundation of China [31972900]; National Natural Science Foundation of China [31670901]; Innovative Research Team of High-level Local Universities in Shanghai; National Basic Research Program of China (973 Program) [2018YFC1705505]; National Basic Research Program of China (973 Program) [2016YFC1305103]; Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [TP2016007]; Shanghai Municipal Population and Family Planning Commission [2017YQ012]. We thank Dr. G. Pei (Tongji University) for providing Arrb2 −/- mice, Dr. B.B. Finlay and Dr. Wanyin Deng (University of British Colombia) for C. rodentium and C. rodentium Δtir strains, Dr. J. Leong (Tufts University School of Medicine) for Tir cDNA, JPN15, JPN15∆Tir, and JPN15 (∆tir + HA-tir) strains. We thank members of the D. Y. laboratory for helpful discussions and technical assistance.

FundersFunder number
Innovative Research Team of High-level Local Universities in Shanghai
Tufts University School of Medicine
National Natural Science Foundation of China31972900, 31670901
Tongji University
University of British Columbia
Shanghai Municipal Population and Family Planning Commission2017YQ012
National Key Research and Development Program of China2016YFC1305103, 2018YFC1705505
Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher LearningTP2016007

    Keywords

    • EPEC
    • TAK1
    • TLR signaling
    • TRAF6
    • immune evasion
    • β-arrestin 2

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