TIR domain-associated nucleotides with functions in plant immunity and beyond.

TIR (Toll/interlukin-1 receptor) domains are found in archaea, bacteria and eukaryotes, featured in proteins generally associated with immune functions. In plants, they are found in a large group of NLRs (nucleotide-binding leucine-rich repeat receptors), NLR-like proteins and TIR-only proteins. They are also present in effector proteins from phytopathogenic bacteria that are associated with suppression of host immunity. TIR domains from plants and bacteria are enzymes that cleave NAD+ (nicotinamide adenine dinucleotide, oxidized form) and other nucleotides. In dicot plants, TIR-derived signalling molecules activate downstream immune signalling proteins, the EDS1 (enhanced disease susceptibility 1) family proteins, and in turn helper NLRs. Recent work has brought major advances in understanding how TIR domains work, how they produce signalling molecules and how these products signal.

SARM1-Dependent Axon Degeneration: Nucleotide Signaling, Neurodegenerative Disorders, Toxicity, and Therapeutic Opportunities.

Axons are an essential component of the nervous system, and axon degeneration is an early feature of many neurodegenerative disorders. The NAD+ metabolome plays an essential role in regulating axonal integrity. Axonal levels of NAD+ and its precursor NMN are controlled in large part by the NAD+ synthesizing survival factor NMNAT2 and the pro-neurodegenerative NADase SARM1, whose activation triggers axon destruction. SARM1 has emerged as a promising axon-specific target for therapeutic intervention, and its function, regulation, structure, and role in neurodegenerative diseases have been extensively characterized in recent years. In this review, we first introduce the key molecular players involved in the SARM1-dependent axon degeneration program. Next, we summarize recent major advances in our understanding of how SARM1 is kept inactive in healthy neurons and how it becomes activated in injured or diseased neurons, which has involved important insights from structural biology. Finally, we discuss the role of SARM1 in neurodegenerative disorders and environmental neurotoxicity and its potential as a therapeutic target.

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration.

Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD+, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD+ and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+, thereby inducing feedforward metabolic catastrophe and axonal demise.