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Akkermansia muciniphila SEV-containing proteins smaller than 30 kDa

ABSTRACT: Histone lysine lactylation (Klac) is a new posttranslational modification (PTM) that is installed by acetyltransferase to modulate specific immune responses1 and oncogenesis2,3. Akkermansia muciniphila (A. muciniphila) is a beneficial bacterium that blunts ulcerative colitis (UC) in a mouse model by secreting extracellular vesicles (SEVs)4. Although many histone sites are known to contain lysine lactylation, whether this modification is regulated to modulate specific biological functions by exogenous acetyltransferase or intestinal microbiota is not well understood. Here, we discovered that SEV from A. muciniphila, rather than A. muciniphila per se, has anti-Th17 (T helper 17) differentiation activity. We further screened the composition of SEV and found that Amuc_2172 is the key active component. As a GCN5-related acetyltransferase of A. muciniphila, Amuc_2172 is accessible to naïve T cells and functions as a lactylation transferase on Lys4 of histone H3. Accelerated histone H3 lactylation (H3Klac) on Lys4 competitively blocks trimethylation (H3Kme3) on Il17a loci in the process of Th17-cell differentiation. Additionally, intraperitoneal application of recombinant Amuc_2172 also inhibited Th17 and dextran sulfate sodium (DSS)-induced UC phenotypes in vivo; moreover, bioengineered Amuc_2172 showed improved colitis site delivery and higher Th17 inhibition potential compared to Amuc_2172 alone. Our study reveals not only a potential therapeutic strategy for treating colitis but also a model via which lysine lactylation is regulated by the intestinal microbiota, which may be broadly applicable to understand the crosstalk of bacteria and immunity.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Akkermansia Muciniphila

SUBMITTER: Qian Zhou

LAB HEAD: Mingming Zhang

PROVIDER: PXD037100 | Pride | 2023-11-28

REPOSITORIES: Pride

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Project description:In patients with severe kidney disease AVF are surgically placed in order to create good access for hemodialysis. In these dialysis patients the failure rates of AVF can be as high as 24% within 6 months after surgery, causing ineffective dialysis and necessitating additional clinical interventions. The pathological processes known to lead to AVF failure are beginning to be unravelled include the formation of venous neointimal hyperplasia (VNIH), thrombosis (Chang et al. PMID 16105066), and venous stenosis (Kanterman et al. PMID7892454, Tang et al. 1998), resulting in a reduced blood flow through the fistula. We established a rat model for AVF failure in human kidney dialysis patients. The characterization of this model has been previously described (Globerman et al. 2011, PubmedID:22002501). In this model the AVFs are surgically constructed in the right leg by connecting the superficial epigastric vein SEV to the common femoral artery (CFA), resulting in exposure of the SEV to arterial pressure with pulsatile and low resistant flow patterns (Globerman et al. 2011, PMID22002501). In the present study we utilized this AVF model in order to assess the effects of arterialized flow, with consequent pathological changes of the vessel wall due to surgical AVF instalment, on the transcriptome of endothelium from the SEV. Within the SEV these pathologies of the vessel wall include the formation of NIH in the main branch, and stenosis in the side branches. By employing this rat model we assessed the changes of the endothelial transcriptome in relation to these pathologies in order to gain mechanistic understanding of the potential roles of venous endothelium in AVF failure, as well as to identify potential biomarkers preceding AVF failure. AVF surgery was performed on N=6 rats, and 13-14 days after surgery the rats were sacrificed. AVFs were extracted from the rats, and microarray transcriptome analyses were performed on luminal endothelial cells that isolated from four different sites of the AVF by employing Laser Capture Microdissection (LCM). These sites included (i) N=5 AVF sections of the superficial epigastric vein (SEV) with neointimal hyperplasia (NIH), (ii) N=3 AVF sections of SEV side branches with luminal stenosis, (iii), N=6 sections of the SEV located distally from a ligation thereby omitting exposure to arterialized flow and consequently preventing the development of NIH or stenosis, and (iv) N=3 sections of the AVF common femoral artery without signs of NIH or stenosis.

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Akkermansia muciniphila SEV-containing proteins smaller than 30 kDa

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