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 language | English |
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Pages (from-to) | 1423-1437 |
Number of pages | 15 |
Journal | Gut Microbes |
Volume | 11 |
Issue number | 5 |
DOIs | |
State | Published - 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.
Funders | Funder number |
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Innovative Research Team of High-level Local Universities in Shanghai | |
Tufts University School of Medicine | |
National Natural Science Foundation of China | 31972900, 31670901 |
Tongji University | |
University of British Columbia | |
Shanghai Municipal Population and Family Planning Commission | 2017YQ012 |
National Key Research and Development Program of China | 2016YFC1305103, 2018YFC1705505 |
Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning | TP2016007 |
Keywords
- EPEC
- TAK1
- TLR signaling
- TRAF6
- immune evasion
- β-arrestin 2