bims-meprid 2023-09-10 papers

Issue of 2023‒09‒10
six papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

bioRxiv. 2023 Aug 26. pii: 2023.08.26.554955. [Epub ahead of print]

Glycolytic Metabolon Assembly on Mitochondria via Hexokinase O-GlcNAcylation Promotes Metabolic Efficiency.

Haoming Wang, John Vant, Youjun Wu, Richard Sánchez, Mary Lauren Micou, Andrew Zhang, Vincent Luczak, Seungyoon Blenda Yu, Mirna Jabbo, Seokjun Yoon, Ahmed Abdallah Abushawish, Majid Ghassemian, Eric Griffis, Marc Hammarlund, Abhishek Singharoy, Gulcin Pekkurnaz.

Glucose is the primary cellular energy substrate and its metabolism via glycolysis is initiated by the rate-limiting enzyme Hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the prominent isoform, primarily localized on mitochondria, crucial for the efficient coupling of glycolysis and oxidative phosphorylation, thereby ensuring optimal energy generation. Here, we reveal a novel regulatory mechanism whereby metabolic sensor enzyme O-GlcNAc transferase (OGT) modulates HK1 activity and its mitochondrial association. OGT catalyzes reversible O-GlcNAcylation, a post-translational modification, influenced by glucose flux-mediated intracellular UDP-GlcNAc concentrations. Dynamic O-GlcNAcylation of HK1's regulatory domain occurs with increased OGT activity, promoting glycolytic metabolon assembly on the outer mitochondrial membrane. This modification enhances HK1's mitochondrial localization, orchestrating glycolytic and mitochondrial ATP production. Mutations in HK1's O-GlcNAcylation site reduce ATP generation, affecting presynaptic vesicle release in neurons. Our findings reveal a new pathway linking neuronal metabolism to mitochondrial function through OGT and glycolytic metabolon formation, and provide important insight into the previously unknown metabolism plasticity mechanism.

DOI: https://doi.org/10.1101/2023.08.26.554955

J Biol Chem. 2023 Sep 01. pii: S0021-9258(23)02248-2. [Epub ahead of print] 105220

Inhibition of mitochondrial fatty acid β-oxidation activates mTORC1 pathway and protein synthesis via Gcn5-dependent acetylation of raptor in zebrafish.

Wen-Hao Zhou, Yuan Luo, Rui-Xin Li, Pascal Degrace, Tony Jourdan, Fang Qiao, Li-Qiao Chen, Mei-Ling Zhang, Zhen-Yu Du.

Pharmacological inhibition of mitochondrial fatty acid oxidation (FAO) has been clinically used to alleviate certain metabolic diseases by remodeling cellular metabolism. However, mitochondrial FAO inhibition also leads to mTORC1 activation-related protein synthesis and tissue hypertrophy, but the mechanism remains unclear. Here, by using a mitochondrial FAO inhibitor (Mildronate or Etomoxir) or knocking out carnitine palmitoyltransferase-1, we revealed that mitochondrial FAO inhibition activated the mTORC1 pathway through Gcn5-dependent Raptor acetylation. Mitochondrial FAO inhibition significantly promoted glucose catabolism and increased intracellular acetyl-CoA levels. In response to the increased intracellular acetyl-CoA, acetyltransferase Gcn5 activated mTORC1 by catalyzing Raptor acetylation through direct interaction. Further investigation also screened Raptor deacetylases HDAC class II and identified HDAC7 as a potential regulator of Raptor. These results provide a possible mechanistic explanation for the mTORC1 activation after mitochondrial FAO inhibition and also bring light to reveal the roles of nutrient metabolic remodeling in regulating protein acetylation by affecting acetyl-CoA production.

Keywords: Gcn5; Raptor; acetyl-CoA; mTORC1; mitochondrial FAO inhibition

DOI: https://doi.org/10.1016/j.jbc.2023.105220

Mol Cell Proteomics. 2023 Sep 05. pii: S1535-9476(23)00152-4. [Epub ahead of print] 100641

Lactate and lactylation: Clinical applications of routine carbon source and novel modification in human diseases.

Zhimin Wang, Dan Hao, Shuiying Zhao, Ziyin Zhang, Zhen Zeng, Xiao Wang.

Cell metabolism generates numerous intermediate metabolites that could serve as feedback and feed-forward regulation substances for post-translational modification. Lactate, a metabolic product of glycolysis, has recently been conceptualized to play a pleiotropic role in shaping cell identities through metabolic rewiring and epigenetic modifications. Lactate-derived carbons, sourced from glucose, mediate the crosstalk among glycolysis, lactate and lactylation. Furthermore, the multiple metabolic fates of lactate make it an ideal substrate for metabolic imaging in clinical application. Several studies have identified the crucial role of protein lactylation in human diseases associated with cell fate determination, embryonic development, inflammation, neoplasm and neuropsychiatric disorders. Herein, this review will focus on the metabolic fate of lactate-derived carbon to provide useful information for further research and therapeutic approaches in human diseases. We comprehensively discuss its role in reprogramming and modification during the regulation of glycolysis, the clinical translation prospects of the hyperpolarized lactate signal, lactyl modification in human diseases, and its application with other techniques and omics.

Keywords: Lactate; clinical application; human disease; lactylation; post transcriptional modification

DOI: https://doi.org/10.1016/j.mcpro.2023.100641

Front Immunol. 2023 ;14 1209970

Protein O-GlcNAcylation in multiple immune cells and its therapeutic potential.

Huanhuan Cai, Wei Xiong, Haoyan Zhu, Qiongxin Wang, Shi Liu, Zhibing Lu.

O-GlcNAcylation is a post-translational modification of proteins that involves the addition of O-GlcNAc to serine or threonine residues of nuclear or cytoplasmic proteins, catalyzed by O-GlcNAc transferase (OGT). This modification is highly dynamic and can be reversed by O-GlcNAcase (OGA). O-GlcNAcylation is widespread in the immune system, which engages in multiple physiologic and pathophysiologic processes. There is substantial evidence indicating that both the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation are critically involved in regulating immune cell function. However, the precise role of O-GlcNAcylation in the immune system needs to be adequately elucidated. This review offers a thorough synopsis of the present research on protein O-GlcNAcylation, accentuating the molecular mechanisms that control immune cells' growth, maturation, and performance via this PTM.

Keywords: O-GlcNAcylation; OGA; OGT; immune cells; innate immunity

DOI: https://doi.org/10.3389/fimmu.2023.1209970

J Eur Acad Dermatol Venereol. 2023 Sep 05.

Serine deficiency exacerbates psoriatic skin inflammation by regulating S-adenosyl methionine-dependent DNA methylation and NF-κB signaling activation in keratinocytes.

Qinqin Meng, Ying Liu, Leiqing Yao, Zhimiao Ma, Lu Guo, Ting Hu, Yixin Luo, Jiaoling Chen, Erle Dang, Zhengxiao Li.

BACKGROUND: Serine metabolism is crucial for tumor oncogenesis and immune responses. S-adenosyl methionine (SAM), a methyl donor, is typically derived from serine-driven one-carbon metabolism. However, the involvement of serine metabolism in psoriatic skin inflammation remains unclear.OBJECTIVES: To investigate the association between serine metabolism and psoriatic skin inflammation.
METHODS: Clinical samples were collected from patients with psoriasis and the expression of serine biosynthesis enzymes was evaluated. The HaCaT human keratinocyte cell line was transfected with small interfering RNA (siRNA) of key enzyme or treated with inhibitors. RNA sequencing and DNA methylation assays were performed to elucidate the mechanisms underlying serine metabolism-regulated psoriatic keratinocyte inflammation An imiquimod (IMQ)-induced psoriasis mouse model was established to determine the effect of the SAM administration on psoriatic skin inflammation.
RESULTS: The expression of serine synthesis pathway enzymes, including the first rate-limiting enzyme in serine biosynthesis, phosphoglycerate dehydrogenase (PHGDH), was downregulated in the epidermal lesions of patients with psoriasis compared with that in healthy controls. Suppressing PHGDH in keratinocytes promoted the production of proinflammatory cytokines and enrichment of psoriatic-related signaling pathways, including the tumor necrosis factor-alpha (TNF-α) signaling pathway, interleukin (IL)-17 signaling pathway, and NF-κB signaling pathway. In particular, PHGDH inhibition markedly promoted the secretion of IL-6 in keratinocytes with or without IL-17A, IL-22, IL-1α, oncostatin M, and TNF-α (mix) stimulation. Mechanistically, PHGDH inhibition upregulated the expression of IL-6 by inhibiting SAM-dependent DNA methylation at the promoter and increasing the binding of myocyte enhancer factor 2A. Furthermore, PHGDH inhibition increased the secretion of IL-6 by increasing the activation of NF-κB via SAM inhibition. SAM treatment effectively alleviated IMQ-induced psoriasis-like skin inflammation in mice.
CONCLUSIONS: Our study revealed the crucial role of PHGDH in antagonizing psoriatic skin inflammation and indicated that targeting serine metabolism may represent a novel therapeutic strategy for treating psoriasis.

Keywords: S-adenosyl methionine; inflammation; keratinocyte; phosphoglycerate dehydrogenase; psoriasis

DOI: https://doi.org/10.1111/jdv.19492

Cell Death Dis. 2023 09 06. 14(9): 591

METTL16 controls Kaposi's sarcoma-associated herpesvirus replication by regulating S-adenosylmethionine cycle.

Xinquan Zhang, Wen Meng, Jian Feng, Xinghong Gao, Chao Qin, Pinghui Feng, Yufei Huang, Shou-Jiang Gao.

Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related cancers. As one of the most abundant RNA modifications, N6-methyladenosine (m6A) and its related complexes regulate KSHV life cycle. However, the role of METTL16, a newly discovered RNA methyltransferase, in KSHV life cycle remains unknown. In this study, we have identified a suppressive role of METTL16 in KSHV lytic replication. METTL16 knockdown increased while METTL16 overexpression reduced KSHV lytic replication. METTL16 binding to and writing of m6A on MAT2A transcript are essential for its splicing, maturation and expression. As a rate-limiting enzyme in the methionine-S-adenosylmethionine (SAM) cycle, MAT2A catalyzes the conversion of L-methionine to SAM required for the transmethylation of protein, DNA and RNA, transamination of polyamines, and transsulfuration of cystathionine. Consequently, knockdown or chemical inhibition of MAT2A reduced intracellular SAM level and enhanced KSHV lytic replication. In contrast, SAM treatment was sufficient to inhibit KSHV lytic replication and reverse the effect of the enhanced KSHV lytic program caused by METTL16 or MAT2A knockdown. Mechanistically, METTL16 or MAT2A knockdown increased while SAM treatment decreased the intracellular reactive oxygen species level by altering glutathione level, which is essential for efficient KSHV lytic replication. These findings demonstrate that METTL16 suppresses KSHV lytic replication by modulating the SAM cycle to maintain intracellular SAM level and redox homeostasis, thus illustrating the linkage of KSHV life cycle with specific m6A modifications, and cellular metabolic and oxidative conditions.

DOI: https://doi.org/10.1038/s41419-023-06121-3