Structural basis of signalling by TIR domain containing proteins

TL;DR

This paper explores how TIR domains in immune proteins function, revealing their role in signaling and disease, with potential for new therapies.

Contribution

The study provides new structural and mechanistic insights into TIR domain signaling across species and disease contexts.

Findings

TIR domains have self-association-dependent enzymatic activities that produce immune signaling molecules.

Structural models of TIR signalosomes explain TLR signaling and SARM1 activation.

Novel immune signaling molecules were identified, including their role in bacterial antiphage defense.

Abstract

The Toll/interleukin-1 receptor (TIR) domain is found in animal, plant and bacterial immune systems, and function through self-association and homotypic interactions with other TIR domains. [1]. It was first described as a protein-protein interaction module mediating signalling downstream of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families in animals. However, studies of the neurodegenerative disease therapeutic target SARM1, plant immune receptors, and many bacterial TIR domain-containing proteins revealed that TIR domains have self- association-dependent enzymatic activities [2] and can produce diverse signaling molecules using nicotinamide adenine dinucleotide (NAD+) as a substrate. We have reconstituted TIR domain signalosomes and characterised them using an integrative structural biology approach combining MicroED, cryoEM, NMR, site directed mutagenesis, cellular assays and chemical tools. Our results have provided structural insight into TLR signal transduction [3-4] and revealed mechanisms of SARM1 activation, NAD+ cleavage and inhibition [5-6] as well as chemical structures of novel immune signalling molecules and their role in bacterial antiphage defence systems [7-8]. Collectively, our studies have led to new models for signal transduction in response to infection and provided rational avenues for the design of new therapeutics to combat a range of neurodegenerative diseases.