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

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.

• Authors: Zijuan Chen, Ruixue Zhou, Yihua Zhang, Doudou Hao, Yu Wang, Shichao Huang, Ningning Liu, Chunmei Xia, Nissan Yissachar, Feng Huang, Yiwei Chu, Dapeng Yan
• Journal: Gut microbes (Gut Microbes) Vol. 11 Issue 5 Pg. 1423-1437 (09 02 2020) ISSN: 1949-0984 [Electronic] United States
• PMID: 32403971 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arrb2 protein, mouse
• Cytokines
• Escherichia coli Proteins
• RNA, Small Interfering
• Receptors, Cell Surface
• TNF Receptor-Associated Factor 6
• Tir protein, E coli
• Toll-Like Receptors
• beta-Arrestin 2
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• Protein Tyrosine Phosphatase, Non-Receptor Type 6
• Ptpn6 protein, mouse

Topics

• Amino Acid Motifs
• Animals
• Cells, Cultured
• Cytokines (genetics, metabolism)
• Enteropathogenic Escherichia coli (immunology, metabolism, pathogenicity)
• Escherichia coli Proteins (chemistry, metabolism)
• HEK293 Cells
• HeLa Cells
• Humans
• Immune Evasion
• MAP Kinase Kinase Kinases (metabolism)
• Macrophages (microbiology)
• Macrophages, Peritoneal (microbiology)
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Protein Binding
• Protein Tyrosine Phosphatase, Non-Receptor Type 6 (metabolism)
• RAW 264.7 Cells
• RNA, Small Interfering
• Receptors, Cell Surface (chemistry, metabolism)
• Signal Transduction
• TNF Receptor-Associated Factor 6 (genetics, metabolism)
• Toll-Like Receptors (metabolism)
• beta-Arrestin 2 (genetics, metabolism)