Journal article
SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation
Proceedings of the National Academy of Sciences of the United States of America, Vol.113(41), pp.E6271-E6280
PNAS Plus
10/11/2016
DOI: 10.1073/pnas.1601506113
PMCID: PMC5068253
PMID: 27671644
Abstract
Axon degeneration is an important pathological event in multiple neurodegenerative disorders. Axon injury stimulates the prodestructive factor SARM1, leading to the precipitous loss in the metabolite NAD
+
. Remarkably, enforcing dimerization of the Toll/interleukin receptor (TIR) domain from SARM1 is sufficient to promote NAD
+
loss and axon degeneration. In this study, we uncover fundamental elements within the SARM1 TIR domain responsible for this activity, including a unique motif that is highly specific to SARM1. In addition, we discover a role for the SARM1 TIR domain in injury-induced activation of the SARM1 protein, suggesting that this domain contributes to SARM1 regulation in addition to the execution of axon degeneration. These studies identify potential avenues for therapeutic intervention in SARM1-dependent axon destruction pathways.
Axon injury in response to trauma or disease stimulates a self-destruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD
+
and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD
+
loss and axon degeneration. Dimerization of the TIR domain from the
Caenorhabditis elegans
SARM1 ortholog TIR-1 leads to NAD
+
loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD
+
loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.
Details
- Title: Subtitle
- SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation
- Creators
- Daniel W Summers - Washington University in St. LouisDaniel A Gibson - Washington University in St. LouisAaron DiAntonio - Washington University in St. LouisJeffrey Milbrandt - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences of the United States of America, Vol.113(41), pp.E6271-E6280
- Publisher
- National Academy of Sciences
- Series
- PNAS Plus
- DOI
- 10.1073/pnas.1601506113
- PMID
- 27671644
- PMCID
- PMC5068253
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- AG013730 / HHS | National Institutes of Health (NIH) NS087632 / HHS | National Institutes of Health (NIH) 344513 / Muscular Dystrophy Association (MDA) NS065053 / HHS | National Institutes of Health (NIH) NS092447 / HHS | National Institutes of Health (NIH)
- Alternative title
- Motifs in SARM1 TIR domain enable NAD+ loss
- Language
- English
- Date published
- 10/11/2016
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9983992087202771
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