Immune dysregulation and <scp>RNA N6</scp>‐methyladenosine modification in sepsis

Chen, Hongyan; Zhang, Xiaoting; Su, Hao; Zeng, Judeng; Chan, Hung; Li, Qing; Liu, Xiaodong; Zhang, Lin; Wu, William; Chan, Matthew T. V.; Chen, Huarong

doi:10.1002/wrna.1764

Cited by 10 publications

(5 citation statements)

References 154 publications

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“…Growing evidence suggests that PTMs can be a cornerstone in regulating cell functions and multiple diseases, including sepsis. However, the mechanisms by which an infection induces specific protein PTMs and protein PTMs lead to inflammatory disorders, cytokine storm, and organ dysfunction remain unclear. We previously reported LPS-induced proteome and acetylome data in vitro and indicated the functional regulation of lysine-acetylated PKM2 in SALD .…”

Section: Discussionmentioning

confidence: 99%

Integrative Profiling of Lysine Acylome in Sepsis-Induced Liver Injury

Na,

Choi,

Paudel

et al. 2023

J. Proteome Res.

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Sepsis is one of the life-threatening diseases worldwide. Despite the continuous progress in medicine, the specific mechanism of sepsis remains unclear. A key strategy of pathogens is to use post-translational modification to modulate host factors critical for infection. We employed global immunoprecipitation technology for lysine acetylation (Kac), succinylation (Ksu), and malonylation (Kmal) for the first global lysine acylation (Kacy) analysis in a cecum ligation and puncture (CLP) model in mouse. This was performed to reveal the pathogenic mechanism of integrative Kacy and the changes in modification sites. In total, 2230 sites of 1,235 Kac proteins, 1,887 sites of 433 Ksu proteins, and 499 sites of 276 Kmal proteins were quantified and normalized by their protein levels. We focused on 379 sites in 219 upregulated proteins as the integrative Kacy sites of Kac, Ksu, and Kmal on the basis of sirtuins decreased in the CLP group. KEGG pathway analysis of integrative Kacy in 219 upregulated proteins revealed three central metabolic pathways: glycolysis/gluconeogenesis, pyruvate metabolism, and tricarboxylic acid cycle. These findings reveal the key pathogenic mechanism of integrative PTM alteration in terms of the decreased sirtuins level and provide an important foundation for an in-depth study of the biological function of Kacy in sepsis.

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Section: Discussionmentioning

confidence: 99%

Integrative Profiling of Lysine Acylome in Sepsis-Induced Liver Injury

Na,

Choi,

Paudel

et al. 2023

J. Proteome Res.

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“…m6A modi cation can orchestrate the development, differentiation, and activation of immune cells, consequently affecting the host defense and in ammatory responses to pathogens 11 . Dysregulated m6A modi cations contribute to the pathogenesis of immune-related diseases 12 . In addition, many studies have reported the role of m6A methylation in programmed cell death including apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis 13 .…”

Section: Introductionmentioning

confidence: 99%

METTL3 Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Activating the MAPK Signaling Pathway

Gao,

Wang,

Qin

et al. 2024

Preprint

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Inflammatory responses, apoptosis, and oxidative stress, are key factors that contribute to hepatic ischemia/reperfusion (I/R) injury, which may lead to the failure of liver surgeries, such as hepatectomy and liver transplantation. The N6-methyladenosine (m6A) modification has been implicated in multiple biological processes, and its specific role and mechanism in hepatic I/R injury require further investigation. This study focused on the role of RNA methylase METTL3 in hepatic ischemia-reperfusion injury. Dot blotting analysis was used to profile m6A levels in liver tissues at different reperfusion time points in hepatic I/R mouse models. Hepatocyte-specific METTL3 knockdown (HKD) mice were used to determine the function of METTL3 during hepatic I/R. RNA sequencing and western blotting were performed to assess the potential signaling pathways involved with the deficiency of METTL3. Finally, AAV8-TBG-METTL3 was injected through the tail vein to further elucidate the role of METTL3 in hepatic I/R injury. We found that the m6A modification levels and the expression of METTL3 were upregulated in mouse livers during hepatic I/R injury. METTL3 deficiency led to an exacerbated inflammatory response and increased cell death during hepatic I/R, whereas overexpression of METTL3 reduced the extent of liver injury. Bioinformatic analysis revealed that the MAPK pathway was significantly enriched in the livers of METTL3-deficient mice. METTL3 protected the liver from I/R injury, possibly by inhibiting the phosphorylation of JNK and ERK, but not P38.

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“…m 6 A modification can orchestrate the development, differentiation, and activation of immune cells, consequently affecting the host defense and inflammatory responses to pathogens [11]. Dysregulated m 6 A modifications contribute to the pathogenesis of immune-related diseases [12]. In addition, many studies have reported the role of m 6 A methylation in programmed cell death including apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis [13].…”

Section: Introductionmentioning

confidence: 99%

METTL3 Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Activating the MAPK Signaling Pathway

Gao,

Wang,

Qin

et al. 2024

Int. J. Med. Sci.

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Background: Inflammatory responses, apoptosis, and oxidative stress, are key factors that contribute to hepatic ischemia/reperfusion (I/R) injury, which may lead to the failure of liver surgeries, such as hepatectomy and liver transplantation. The N6-methyladenosine (m 6 A) modification has been implicated in multiple biological processes, and its specific role and mechanism in hepatic I/R injury require further investigation. Methods: Dot blotting analysis was used to profile m 6 A levels in liver tissues at different reperfusion time points in hepatic I/R mouse models. Hepatocyte-specific METTL3 knockdown (HKD) mice were used to determine the function of METTL3 during hepatic I/R. RNA sequencing and western blotting were performed to assess the potential signaling pathways involved with the deficiency of METTL3. Finally, AAV8-TBG-METTL3 was injected through the tail vein to further elucidate the role of METTL3 in hepatic I/R injury. Results: The m 6 A modification levels and the expression of METTL3 were upregulated in mouse livers during hepatic I/R injury. METTL3 deficiency led to an exacerbated inflammatory response and increased cell death during hepatic I/R, whereas overexpression of METTL3 reduced the extent of liver injury. Bioinformatic analysis revealed that the MAPK pathway was significantly enriched in the livers of METTL3-deficient mice. METTL3 protected the liver from I/R injury, possibly by inhibiting the phosphorylation of JNK and ERK, but not P38. Conclusions: METTL3 deficiency aggravates hepatic I/R injury in mice by activating the MAPK signaling pathway. METTL3 may be a potential therapeutic target in hepatic I/R injury.

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Immune dysregulation and RNA N6‐methyladenosine modification in sepsis

Cited by 10 publications

References 154 publications

Integrative Profiling of Lysine Acylome in Sepsis-Induced Liver Injury

Integrative Profiling of Lysine Acylome in Sepsis-Induced Liver Injury

METTL3 Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Activating the MAPK Signaling Pathway

METTL3 Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Activating the MAPK Signaling Pathway

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