-
Views
-
Cite
Cite
Kow Essuman, Li Wan, Daniel W Summers, Ryan G Anderson, Yo Sasaki, Xianrong Mao, Aldrin Kay Yuen Yim, Freddy Monteiro, Eui-Hwan Chung, Erin Osborne-Nishimura, Jeffery Dangl, Marc Nishimura, Aaron DiAntonio, Jeffrey Milbrandt, Redefining the TIR domain: From Axon Degeneration to Innate Immunity and Beyond, The Journal of Immunology, Volume 202, Issue 1_Supplement, May 2019, Page 64.1, https://doi.org/10.4049/jimmunol.202.Supp.64.1
Close - Share Icon Share
Abstract
The Toll/Interleukin-1 Receptor (TIR) domain is an evolutionary ancient protein domain, present in numerous receptors and adaptor proteins, and is the signature-signaling domain of Toll-Like Receptors (TLRs). In animals, these TIR domains generally serve as scaffolds that promote the assembly of signaling complexes to trigger activation of pro-inflammatory cytokines and other defense-related products. In plants, TIR domain proteins are known to mediate disease resistance against pathogens, and trigger hypersensitive cell death. However, their mechanism of action has remained elusive. In bacteria, TIR domains have been associated with virulence and defense against some viruses. Here, we redefine the canonical scaffolding function of the TIR domain by showing that TIR domains can possess intrinsic enzymatic activity, and constitute a family of enzymes that cleave the essential metabolic cofactor Nicotinamide Adenine Dinucleotide (NAD+). We identify the TIR domain of SARM1 as the founding member of the TIR NADase family that triggers axon self-destruction upon axonal injury. We show that the TIR enzymatic activity in conserved in bacteria, and archaea, where in bacteria this NADase activity has recently been linked to defense against viruses. Finally, we extend our findings to plant innate immunity, and show that plant TIR-domain Immune Receptors trigger cell death and transduce recognition of pathogens into an immune response via this conserved enzymatic activity. Altogether, our findings establish TIR domain proteins as a new family of metabolic enzymes, and we posit that the scaffolding function in TLR signaling likely represents a repurposing of this evolutionary ancient enzymatic function.
