Biology subjects

Morehouse, B. R.

Publications and source records attributed to Morehouse, B. R..

3 recordsLinked to original sources

bioRxiv2024

A human homolog of SIR2 antiphage proteins mediates immunity via the TLR pathway

The full extent of immune system conservation between prokaryotes and eukaryotes is unknown. However, recent research supports that a subset of bacterial antiphage proteins is conserved in eukaryotes and likely gave rise to key actors of mammalian immunity. Here, we show that the SIR2 protein domain, present in bacterial antiphage systems, plays a role in eukaryotic innate immunity. Through phylogenetic analysis, we identify SIRanc, a human protein with a SIRim domain (subtype of SIR2). We demonstrate that SIRanc plays a pivotal role in the animal toll-like receptor (TLR) pathway of innate immunity by mediating the transcriptional upregulation of proinflammatory genes downstream of TLR stimulation. This depends on the enzymatic activity of SIRanc, which degrades NAD+, a central cellular metabolite. Finally, we show that proteins with a SIRim domain are diverse and widespread, detected in 19% of eukaryotic genomes, with SIRanc representing one of the five sirim lineages. This work opens avenues of research on the potential role of eukaryotic SIRim proteins in immunity, as well as on the involvement of SIRanc in human pathology.

immunology↗

bioRxiv2023

cGLRs are a diverse family of pattern recognition receptors in animal innate immunity

cGAS (cyclic GMP-AMP synthase) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2'3'-cGAMP that activates the protein STING and downstream immunity. Here we discover cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in animal innate immunity. Building on recent analysis in Drosophila, we use a bioinformatic approach to identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screen of 140 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of alternative nucleotide signals including isomers of cGAMP and cUMP-AMP. Using structural biology, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Together our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.

biochemistry↗

bioRxiv2022

Viruses inhibit TIR gcADPR signaling to overcome bacterial defense

The Toll/interleukin-1 receptor (TIR) domain is a key component of immune receptors that identify pathogen invasion in bacteria, plants, and animals. In the bacterial antiphage system Thoeris, as well as in plants, recognition of infection stimulates TIR domains to produce an immune signaling molecule whose molecular structure remained elusive. This molecule binds and activates the Thoeris immune effector, which then executes the immune function. We identified a large family of phage-encoded proteins, denoted here Thoeris anti-defense 1 (Tad1), that inhibit Thoeris immunity. We found that Tad1 proteins are "sponges" that bind and sequester the immune signaling molecule produced by TIR-domain proteins, thus decoupling phage sensing from immune effector activation and rendering Thoeris inactive. A high-resolution crystal structure of Tad1 bound to the signaling molecule revealed that its chemical structure is 1'-2' glycocyclic ADPR (gcADPR), a unique molecule not previously described in other biological systems. Our results define the chemical structure of a central immune signaling molecule, and reveal a new mode of action by which pathogens can suppress host immunity.

microbiology↗