Project description:Innate immunity in bacteria, plants and animals requires the specialized subset of TIR-domain proteins that are NAD+ hydrolases. Aggregation of these TIR proteins engages their enzymatic activity, but it is not known how this protein multimerization is regulated. Here, we discovered that TIR oligomerization is exquisitely controlled to prevent immune toxicity. We found that p38 propagates its own activation by promoting the feedforward expression and aggregation of the lone enzymatic TIR protein in the nematode C. elegans, TIR-1/SARM1. We performed a forward genetic screen to determine how the p38 positive feedforward loop is regulated. We discovered that the integrity of the specific lysosomal sub-compartment that expresses TIR-1/SARM1 is actively maintained to limit inappropriate aggregation of this protein and restrain toxic p38 immune activation. Thus, innate immune defenses in intestinal epithelial cells are regulated by specific control of TIR-1/SARM1 multimerization.

2024-09-18 | GSE256356 | GEO

EHEC Tir regulate the expression of genes in primary macrophages

Project description:Analysis of total RNA extracted from primary macrophages infected with the bacterial strains of EHEC or EHEC∆Tir. The results showed that Tir might regulate the expression of selected genes.

2018-03-29 | GSE112418 | GEO

Bacteriophage antidefense genes that neutralize TIR and STING immune responses

Project description:Programmed cell suicide of infected bacteria, known as abortive infection (Abi), serves as a central immune defense strategy to prevent the spread of bacteriophage viruses and other invasive genetic elements across a population. Many Abi systems utilize bespoke cyclic nucleotide immune messengers generated upon infection to rapidly mobilize cognate death effectors. Here, we identify a large family of bacteriophage nucleotidyltransferases (NTases) which synthesize competitor cyclic dinucleotide (CDN) ligands and inhibit NAD-depleting TIR effectors activated through a linked STING CDN sensor domain (TIR-STING). Through a functional screen of NTase-adjacent phage genes, we uncover candidate inhibitors of host TIR-STING suicide signaling. Among these, we demonstrate that a virus MazG-like nucleotide pyrophosphatase, Atd1, depletes the starvation alarmone (p)ppGpp, revealing a role for the alarmone-activated host toxin MazF as a key executioner of TIR-driven abortive infection. Phage NTases and counter-defenses like Atd1 preserve host viability to ensure virus propagation, and may be exploited as tools to modulate TIR and STING immune responses.

2023-03-27 | GSE222071 | GEO

LPS-induced TIR domain complex acetylation activated TLR4/MAL/MyD88 signal pathway in sepsis

Project description:Among the diseases caused by Toll-like receptor 4 (TLR4) abnormal activation by bacterial endotoxin, sepsis is the most dangerous one. The reprogramming of macrophages plays a crucial role in orchestrating the pathogenesis of sepsis. However, the precise mechanism underlying TLR4 activation in macrophages remained incompletely understood. Our studies revealed that upon lipopolysaccharide (LPS) stimulation, CREB-binding protein (CBP) was recruited to the TLR4 signalosome complex and resulted in pronounced acetylation in the TIR domains of TLR4, Myeloid differentiation factor 88 (MyD88) and MyD88 adapter-like (MAL), which significantly enhanced the activation of the NF-κB signaling pathway and polarization of M1 macrophages. In sepsis patients, significantly elevated TLR4-TIR acetylation was detected in CD16+ monocytes combined with elevated expression of M1 macrophage markers and production of pro-inflammatory cytokines. In contrast, histone deacetylase 1 (HDAC1) served as a key deacetylase in the deacetylation of the TIR domain complex. The inhibition of HDAC1 accelerated sepsis-associated syndromes, while the inhibition of CBP alleviated this process. Overall, our findings highlighted the crucial role of TIR domain complex acetylation in the regulation of inflammatory immune response and suggested that the reversible acetylation of the complex emerged as a promising therapeutic target for M1 macrophages during the progression of sepsis.

2024-08-01 | PXD052433 | Pride

LPS-induced TIR domain complex acetylation activated TLR4/MAL/MyD88 signal pathway in sepsis [scRNA-Seq]

2024-08-01 | GSE268406 | GEO