The SARM1 TIR domain produces glycocyclic ADPR molecules as minor products.
Autor: | Garb J; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel., Amitai G; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel., Lu A; Department of Microbiology, Harvard Medical School, Boston, MA, United States of America.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, United States of America., Ofir G; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel., Brandis A; Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Mehlman T; Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Kranzusch PJ; Department of Microbiology, Harvard Medical School, Boston, MA, United States of America.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, United States of America.; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA, United States of America., Sorek R; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. |
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Jazyk: | angličtina |
Zdroj: | PloS one [PLoS One] 2024 Apr 18; Vol. 19 (4), pp. e0302251. Date of Electronic Publication: 2024 Apr 18 (Print Publication: 2024). |
DOI: | 10.1371/journal.pone.0302251 |
Abstrakt: | Sterile alpha and TIR motif-containing 1 (SARM1) is a protein involved in programmed death of injured axons. Following axon injury or a drug-induced insult, the TIR domain of SARM1 degrades the essential molecule nicotinamide adenine dinucleotide (NAD+), leading to a form of axonal death called Wallerian degeneration. Degradation of NAD+ by SARM1 is essential for the Wallerian degeneration process, but accumulating evidence suggest that other activities of SARM1, beyond the mere degradation of NAD+, may be necessary for programmed axonal death. In this study we show that the TIR domains of both human and fruit fly SARM1 produce 1''-2' and 1''-3' glycocyclic ADP-ribose (gcADPR) molecules as minor products. As previously reported, we observed that SARM1 TIR domains mostly convert NAD+ to ADPR (for human SARM1) or cADPR (in the case of SARM1 from Drosophila melanogaster). However, we now show that human and Drosophila SARM1 additionally convert ~0.1-0.5% of NAD+ into gcADPR molecules. We find that SARM1 TIR domains produce gcADPR molecules both when purified in vitro and when expressed in bacterial cells. Given that gcADPR is a second messenger involved in programmed cell death in bacteria and likely in plants, we propose that gcADPR may play a role in SARM1-induced programmed axonal death in animals. Competing Interests: P.J.K, R.S, G.A and A.L. are inventors of a patent application related to the production and utility of gcADPR. R.S. is a scientific cofounder and advisor of BiomX and Ecophage. The rest of the authors declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. (Copyright: © 2024 Garb et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.) |
Databáze: | MEDLINE |
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