Date of Award
Doctor of Philosophy (PhD)
The Toll/Interleukin-1 Receptor (TIR) domain is an evolutionarily ancient protein domain conserved from bacteria to eukaryotes, and is an essential signaling component of innate immunity pathways. In animal innate immunity, TIR domains have primarily been described for their scaffolding function in assembling protein complexes in host defense. In plant immunity, TIR domains are key components of the intracellular Nucleotide Binding Leucine rich repeat (NLR) immune receptors that confer resistance to pathogens. These NLR receptors trigger cell death and an immune response upon activation, but their mechanism has remained elusive. In bacteria, TIR domain proteins have been suggested to function as secreted virulence factors against eukaryotic hosts. My dissertation work begins with the study of a TIR domain containing protein, SARM1 (Sterile Alpha and TIR motif containing 1) that is expressed in neurons, and is activated upon axonal injury. SARM1 activation triggers depletion of the essential metabolic cofactor Nicotinamide Adenine Dinucleotide (NAD+), results in energetic failure in the axon, and ultimately axonal death. Since TIR domains were primarily known to function as scaffolds in immune signaling pathways, I embarked on a search for the NAD+ depleting enzyme that was activated by the SARM1 TIR domain, or was binding to the SARM1 TIR scaffold. These studies aimed not only to advance our understanding of the mechanism of axon degeneration, but sought to identify a therapeutic target for diseases characterized by axon degeneration. In my pursuit of this aim, I surprisingly found that rather than activating a secondary NAD+ depleting enzyme, the SARM1 TIR domain itself functioned as the enzyme that depleted axons of NAD+ and caused axonal death. Since TIR domains were not known to possess enzymatic activity, the discovery of the TIR NADase activity in SARM1 placed SARM1 as the founding member of a potentially new class of enzymes. Soon after, I found that the TIR domain enzymatic activity was an ancient enzymatic property, conserved even in bacterial and archaeal TIR domains. Finally, my work has provided significant insights into the biology of plant NLR receptors. We show that TIR domain containing NLR receptors transduce pathogen recognition into cell death via a conserved NAD+ cleavage activity. These findings establish TIR domain proteins as a new family of enzymes, and carries significant implications for innate immunity, and the treatment of diverse neurodegenerative diseases.
Chair and Committee
Marco Colonna, Aaron DiAntonio, Daniel Link, Albert Kim,
Essuman, Kow, "The Enzymatic Function of the TIR domain: From Axon Degeneration to Innate Immunity" (2020). Arts & Sciences Electronic Theses and Dissertations. 2183.