8.A.223.  The Translocated Intimin Receptor (TIR) Family 

Tir is a multifunctional protein that is required for efficient pedestal formation in host epithelial cells during bacterial infection. The extracellular region acts as a receptor for bacterial intimin, allowing the bacterium to attach tightly to the host-cell surface. Simultaneously, the intracellular region initiates a signaling cascade in the host cell, which leads to actin polymerization and formation of actin pedestals at the sites of bacterial adhesion. In strain E2348/69, it acts mainly via the host adaptor proteins NCK1 and NCK2. Once clustered and phosphorylated at Tyr-474, Tir binds to NCK proteins, which in turn bind and activate host WASL/N-WASP, leading to actin polymerization. It can also trigger inefficiently, NCK-independent pedestal formation. This pathway involves phosphorylation of Tyr-454 and probably a putative host adaptor. Tir acts also via direct binding to the host cytoskeletal protein, alpha-actinin, in a NCK- and phosphotyrosine-independent manner. This interaction may stabilize the pedestal, but is not essential for its formation (Kenny 1999).  The transmembrane domains of the type III secretion system effector Tir are involved in its secretion and cellular activities (Braverman et al. 2023). 

Broader functions of TIR domains in Arabidopsis immunity have been identified (Jacob et al. 2023). TIR domains are NAD-degrading enzymes that function during immune signaling in prokaryotes, plants, and animals. In plants, most TIR domains are incorporated into intracellular immune receptors termed TNLs. In Arabidopsis, TIR-derived small molecules bind and activate EDS1 heterodimers, which in turn activate RNLs, a class of cation channel-forming immune receptors. RNL activation drives cytoplasmic Ca2+ influx, transcriptional reprogramming, pathogen resistance, and host cell death. Jacob et al. 2023 screened for mutants that suppress an RNL activation mimic allele and identified a TNL, SADR1. Despite being required for the function of an autoactivated RNL, SADR1 is not required for defense signaling triggered by other tested TNLs. SADR1 is required for defense signaling initiated by some transmembrane pattern recognition receptors and contributes to the unbridled spread of cell death in lesion simulating disease 1. Together with RNLs, SADR1 regulates defense gene expression at infection site borders, likely in a non-cell autonomous manner. RNL mutants that cannot sustain this pattern of gene expression are unable to prevent disease spread beyond localized infection sites, suggesting that this pattern corresponds to a pathogen containment mechanism. SADR1 potentiates RNL-driven immune signaling not only through the activation of EDS1 but also partially independently of EDS1. We studied EDS1-independent TIR function using nicotinamide, an NADase inhibitor. Nicotinamide decreased defense induction from transmembrane pattern recognition receptors and decreased calcium influx, pathogen growth restriction, and host cell death following intracellular immune receptor activation. Jacob et al. 2023 demonstrated that TIR domains can potentiate calcium influx and defense and are thus broadly required for Arabidopsis immunity.


 

References:

Braverman, D., J. Gershberg, and N. Sal-Man. (2023). The transmembrane domains of the type III secretion system effector Tir are involved in its secretion and cellular activities. Front Cell Infect Microbiol 13: 1103552.

Jacob, P., J. Hige, L. Song, A. Bayless, D. Russ, V. Bonardi, F. El Kasmi, L. W√ľnsch, Y. Yang, C.R. Fitzpatrick, B.J. McKinney, M.T. Nishimura, M.R. Grant, and J.L. Dangl. (2023). Broader functions of TIR domains in Arabidopsis immunity. Proc. Natl. Acad. Sci. USA 120: e2220921120.

Kenny, B. (1999). Phosphorylation of tyrosine 474 of the enteropathogenic Escherichia coli (EPEC) Tir receptor molecule is essential for actin nucleating activity and is preceded by additional host modifications. Mol. Microbiol. 31: 1229-1241.

Examples:

TC#NameOrganismal TypeExample
8.A.223.1.1

Translocated intimin receptor, Tir, of a type III protein secretion system, of 550 aas and 2 TMSs at about residues 240 and 570.  See family description for more details.

Tir of E. coli O127:H6 

 
8.A.223.1.2

Tir N-terminal domain-containing protein of 543 aas and 2 TMSs.

Tir of Salmonella enterica

 
8.A.223.1.3

Tir intimin-binding domain-containing protein of 529 aas and 2 TMSs at residues 300 and 420.

Tir of Edwardsiella

 
8.A.223.1.4

Tir of 547 aas and 2 TMSs.  

Tir of Citrobacter rodentium