Journal article
TIR Domain Proteins Are an Ancient Family of NAD+-Consuming Enzymes
Current biology, Vol.28(3), pp.421-430.e4
02/05/2018
DOI: 10.1016/j.cub.2017.12.024
PMCID: PMC5802418
PMID: 29395922
Abstract
The Toll/interleukin-1 receptor (TIR) domain is the signature signaling domain of Toll-like receptors (TLRs) and their adaptors, serving as a scaffold for the assembly of protein complexes for innate immune signaling [1, 2]. TIR domain proteins are also expressed in plants, where they mediate disease resistance [3, 4], and in bacteria, where they have been associated with virulence [5–9]. In pursuing our work on axon degeneration [10], we made the surprising discovery that the TIR domain of SARM1 (sterile alpha and TIR motif containing 1), a TLR adaptor protein, has enzymatic activity [11]. Upon axon injury, the SARM1 TIR domain cleaves nicotinamide adenine dinucleotide (NAD+), destroying this essential metabolic co-factor to trigger axon destruction [11, 12]. Whereas current studies of TIR domains focus on their scaffolding function, our findings with SARM1 inspired us to ask whether this enzymatic activity is the primordial function of the TIR domain. Here we show that ancestral prokaryotic TIR domains constitute a new family of NADase enzymes. Using purified proteins from a cell-free translation system, we find that TIR domain proteins from both bacteria and archaea cleave NAD+ into nicotinamide and ADP-ribose (ADPR), with catalytic cleavage executed by a conserved glutamic acid. A subset of bacterial and archaeal TIR domains generates a non-canonical variant cyclic ADPR (cADPR) molecule, and the full-length TIR domain protein from pathogenic Staphylococcus aureus induces NAD+ loss in mammalian cells. These findings suggest that the primordial function of the TIR domain is the enzymatic cleavage of NAD+ and establish TIR domain proteins as a new class of metabolic regulatory enzymes.
•Multiple bacterial and archaeal TIR domains cleave NAD+ into Nam and ADPR•A subset of prokaryotic TIR domains generates a non-canonical, variant cADPR•The primordial function of the TIR domain is to cleave NAD+•TIR domain proteins are a new family of NAD+-consuming enzymes
Essuman et al. demonstrate that the TIR domains from many prokaryotic proteins possess intrinsic NAD+ cleavage activity. Their findings suggest that the primordial function of the TIR domain is to cleave NAD+, and that this large class of proteins is a central and previously unappreciated regulator of metabolism.
Details
- Title: Subtitle
- TIR Domain Proteins Are an Ancient Family of NAD+-Consuming Enzymes
- Creators
- Kow Essuman - Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USADaniel W Summers - Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USAYo Sasaki - Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USAXianrong Mao - Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USAAldrin Kay Yuen Yim - Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USAAaron DiAntonio - Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USAJeffrey Milbrandt - Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
- Resource Type
- Journal article
- Publication Details
- Current biology, Vol.28(3), pp.421-430.e4
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.cub.2017.12.024
- PMID
- 29395922
- PMCID
- PMC5802418
- ISSN
- 0960-9822
- eISSN
- 1879-0445
- Grant note
- DOI: 10.13039/100000002, name: NIH, award: RF1AG013730, R01NS087632; DOI: 10.13039/100000011, name: Howard Hughes Medical Institute; DOI: 10.13039/100005202, name: Muscular Dystrophy Association, award: MDA344513
- Language
- English
- Date published
- 02/05/2018
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9983992090002771
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