mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity

Pagán, Antonio J.; Lee, Lauren J; Edwards-Hicks, Joy; Moens, Cecilia B.; Tobin, David M.; Busch-Nentwich, Elisabeth M; Pearce, Erika L.; Ramakrishnan, Lalita

doi:10.1016/j.cell.2022.08.018

Cited by 40 publications

(21 citation statements)

References 145 publications

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“…In the current study, we analyzed globally differentially regulated proteins including the down-regulated proteins that are mainly involved in mTOR signaling pathway, NK cell mediated cytotoxicity, P53 signaling pathway, glycoprotein metabolic process, and phosphatidylinositol signaling system. mTOR complex 1 signaling protected macrophages from mycobacterium-triggered cell death by elevating infection-induced energy metabolism ( Pagan et al., 2022 ). The infection of Trueperella pyogenes induced the expression of mTOR and subsequently inhibited the autophagy of host liver cell.…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of lysine crotonylation in human macrophages responding to MRSA infection

Zhang

Ma²,

Liu³

et al. 2023

Front. Cell. Infect. Microbiol.

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Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most commonly encountered bacteria found in healthcare clinics and has been ranked a priority 2 pathogen. Research is urgently needed to develop new therapeutic approaches to combat the pathogen. Variations in the pattern of protein posttranslational modifications (PTMs) of host cells affect physiological and pathological events, as well as therapeutic effectiveness. However, the role of crotonylation in MRSA-infected THP1 cells remains unknown. In this study, we found that crotonylation profiles of THP1 cells were altered after MRSA infection. It was then confirmed that lysine crotonylation profiles of THP1 cells and bacteria were different; MRSA infection inhibited global lysine crotonylation (Kcro) modification but partially elevated Kcro of host proteins. We obtained a proteome-wide crotonylation profile of THP1 cells infected by MRSA further treated by vancomycin, leading to the identification of 899 proteins, 1384 sites of which were down-regulated, and 160 proteins with 193 sites up-regulated. The crotonylated down-regulated proteins were mainly located in cytoplasm and were enriched in spliceosome, RNA degradation, protein posttranslational modification, and metabolism. However, the crotonylated up-regulated proteins were mainly located in nucleus and significantly involved in nuclear body, chromosome, ribonucleoprotein complex, and RNA processing. The domains of these proteins were significantly enriched on RNA recognition motif, and linker histone H1 and H5 families. Some proteins related to protecting against bacterial infection were also found to be targets of crotonylation. The present findings point to a comprehensive understanding of the biological functions of lysine crotonylation in human macrophages, thereby providing a certain research basis for the mechanism and targeted therapy on the immune response of host cells against MRSA infection.

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Section: Discussionmentioning

confidence: 99%

Systematic analysis of lysine crotonylation in human macrophages responding to MRSA infection

Zhang

Ma²,

Liu³

et al. 2023

Front. Cell. Infect. Microbiol.

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“…Cellular metabolism plays a central role in regulation of ISC function and regeneration (17)(18)(19)(20)(21)(22)(23). Emerging data have demonstrated a role for in ammation in causing metabolic adaptations in various immune and non-immune cell targets (24)(25)(26)(27)(28)(29)(30)(31)(32). However, whether ISCs show altered metabolism in the context of in ammation induced stress remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory memory restrains intestinal stem cell regeneration

Reddy

Zhao

Ravikumar

et al. 2023

Preprint

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Intestinal stem cells (ISC) encounter inflammatory insults in immune mediated gastro-intestinal (GI) diseases. It remains unknown whether, and how, they adapt, and if the adaptation leaves scars on the ISCs that affects their subsequent regeneration capacity. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GVHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures demonstrating the persistence of the maladaptive impact of an in vivo inflammatory encounter by the ISCs. Thus, inflammation from GI GVHD leaves a memory of its effects on ISCs that persist and are likely to affect their sensitivity to adapt to future stress or challenges.

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“…EsxA is secreted by ESX-1 and is required for the secretion of the majority of the ESX-1 substrates (1, 14,15). EsxA may play additional roles in the host downstream of phagosomal lysis (16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

An N-acetyltransferase required for EsxA N-terminal protein acetylation and virulence in Mycobacterium marinum.

Collars

Jones

et al. 2023

Preprint

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N-terminal protein acetylation is a ubiquitous post-translational modification that broadly impacts diverse cellular processes in higher organisms. Bacterial proteins are also N-terminally acetylated, but the mechanisms and consequences of this modification in bacteria are poorly understood. We previously quantified widespread N-terminal protein acetylation in pathogenic mycobacteria (C. R. Thompson, M. M. Champion, and P.A. Champion, J Proteome Res 17(9): 3246-3258, 2018, https:// doi: 10.1021/acs.jproteome.8b00373). The major virulence factor EsxA (ESAT-6, Early secreted antigen, 6kDa) was one of the first N-terminally acetylated proteins identified in bacteria. EsxA is conserved in mycobacterial pathogens, including Mycobacterium tuberculosis and Mycobacterium marinum, a non-tubercular mycobacterial species that causes tuberculosis-like disease in ectotherms. However, enzyme responsible for EsxA N-terminal acetylation has been elusive. Here, we used genetics, molecular biology, and mass-spectroscopy based proteomics to demonstrate that MMAR_1839 (renamed Emp1, ESX-1 modifying protein, 1) is the putative N-acetyl transferase (NAT) solely responsible for EsxA acetylation in Mycobacterium marinum. We demonstrated that ERD_3144, the orthologous gene in M. tuberculosis Erdman, is functionally equivalent to Emp1. We identified at least 22 additional proteins that require Emp1 for acetylation, demonstrating that this putative NAT is not dedicated to EsxA. Finally, we showed that loss of emp1 resulted in a significant reduction in the ability of M. marinum to cause macrophage cytolysis. Collectively, this study identified a NAT required for N-terminal acetylation in Mycobacterium and provided insight into the requirement of N-terminal acetylation of EsxA and other proteins in mycobacterial virulence in the macrophage.

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mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity

Cited by 40 publications

References 145 publications

Systematic analysis of lysine crotonylation in human macrophages responding to MRSA infection

Systematic analysis of lysine crotonylation in human macrophages responding to MRSA infection

Inflammatory memory restrains intestinal stem cell regeneration

An N-acetyltransferase required for EsxA N-terminal protein acetylation and virulence in Mycobacterium marinum.

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