The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12

Shen, Haihong; Campanello, Gregory C.; Flicker, Daniel; Grabarek, Zenon; Hu, Jiawei; Luo, Cheng; Banerjee, Ruma; Mootha, Vamsi K.

doi:10.1016/j.cell.2017.09.051

Cited by 118 publications

(125 citation statements)

References 53 publications

(73 reference statements)

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“…Itaconyl‐CoA is an intermediate of itaconate catabolism. It has been reported that itaconate inactivates vitamin B12 in the absence of CLYBL . Mechanistically, knockout of CLYBL promotes the accumulation of itaconyl‐CoA, which directly causes vitamin B12 degradation.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that itaconate inactivates vitamin B12 in the absence of CLYBL. 18 Mechanistically, knockout of CLYBL promotes the accumulation of itaconyl-CoA, which directly causes vitamin B12 degradation. Severe deficiency of vitamin B12 is a common cause of anemia and neurological impairment.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17] More recently, Shen et al showed that itaconate is converted to itaconyl-CoA and then to citramalyl-CoA, which is further catabolized by CLYBL to generate pyruvate and acetyl-CoA, fueling the TCA cycle in LPS-treated RAW 264.7 cells. 18 This provides a route of itaconate catabolism during macrophage activation ( Figure 1a). How itaconate is converted to itaconyl-CoA and whether other catabolic approaches exist, however, are currently unclear.…”

Section: Itaconate Synthesis and Catabolismmentioning

confidence: 99%

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Itaconate: an emerging determinant of inflammation in activated macrophages

Zhang

Zheng

et al. 2018

Immunol Cell Biol

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Macrophages play a central role in innate immunity as the first line of defense against pathogen infection. Upon exposure to inflammatory stimuli, macrophages rapidly respond and subsequently undergo metabolic reprogramming to substantially produce cellular metabolites such as itaconate. As a derivate of the tricarboxylic acid cycle, itaconate is derived from the decarboxylation of cis‐aconitate mediated by immunoresponsive gene 1 in the mitochondrial matrix. It is well known that itaconate has a direct antimicrobial effect by inhibiting isocitrate lyase. Strikingly, two recent studies published in Nature showed that itaconate markedly decreases the production of proinflammatory mediators in lipopolysaccharide‐treated macrophages and ameliorates sepsis and psoriasis in animal models, revealing a novel biological action of itaconate beyond its regular roles in antimicrobial defense. The mechanism for this anti‐inflammatory effect has been proposed to involve the inhibition of succinate dehydrogenase, blockade of IκBζ translation and activation of Nrf2. These intriguing discoveries provide a new explanation for how macrophages are switched from a pro‐ to an anti‐inflammatory state to limit the damage and facilitate tissue repair under proinflammatory conditions. Thus, the emerging effect of itaconate as a crucial determinant of macrophage inflammation has important implications in further understanding cellular immunometabolism and developing future therapeutics for the treatment of inflammatory diseases. In this review, we focus on the roles of itaconate in controlling the inflammatory response during macrophage activation, providing a rationale for future investigation and therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Itaconate Synthesis and Catabolismmentioning

confidence: 99%

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Itaconate: an emerging determinant of inflammation in activated macrophages

Zhang

Zheng

et al. 2018

Immunol Cell Biol

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“…There is only one cluster that includes metazoan sequences, that of the itaconate-detoxifying CLYBL. [25] The Rv2498c cluster is actinobacterial-specific and contains only uncharacterised sequences (seventy-two in UnitProt). A variety of enzymatic activities has been described for PF03328 members, but the majority fall into two classes as it is evident from the tree: aldehyde-lyases (EC:4.1.2) and oxo-acid-lyases (EC:4.1.3); Rv2498c belongs to the latter.…”

Section: Resultsmentioning

confidence: 99%

“…We showed for the first time that Mtb can dissimilate itaconate, a hallmark macrophage metabolite synthesised after lipopolysaccharide activation during host inflammatory response to fight infection and also linked to Vitamin B12 deficiency. [25, 35, 36]. Itaconate is present in some prokaryotes, but its exact physiological function remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a novel stereospecific β-hydroxyacyl-CoA lyase/thioesterase shared by three metabolic pathways inMycobacterium tuberculosis

Wang

Fedorov

et al. 2018

Preprint

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The vast number of poorly characterised enzymes in Mycobacterium tuberculosis (Mtb) is one of the key barriers precluding a better understanding of the biology that underpins pathogenesis. Here, we investigated the Mtb orphan enzyme Rv2498c to delineate its physiological role. Our results from in vitro enzymatic assays, phylogenetic analysis, X-ray crystallography and in vivo Mtb experiments, de-orphan Rv2498c as a multi-functional βhydroxyacyl-CoA lyase/thioesterase (β-HAClyase/thioesterase) that participates in three different metabolic pathways: L-leucine catabolism, itaconate dissimilation, and glyoxylate shunt. Moreover, the deletion of the rv2498c gene from the Mtb genome resulted in attenuation in the mouse model compared to infection with the parent strain. To the best of our knowledge, this is the first report of an (R)-3-hydroxyl-3-methylglutaryl-CoA for leucine catabolism and an itaconate-specific resistance mechanism in Mtb.

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Mitochondrial Function and Dysfunction in White Adipocytes and Therapeutic Implications

Wang,

Huynh,

2024

Comprehensive Physiology

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For a long time, white adipocytes were thought to function as lipid storages due to the sizeable unilocular lipid droplet that occupies most of their space. However, recent discoveries have highlighted the critical role of white adipocytes in maintaining energy homeostasis and contributing to obesity and related metabolic diseases. These physiological and pathological functions depend heavily on the mitochondria that reside in white adipocytes. This article aims to provide an up‐to‐date overview of the recent research on the function and dysfunction of white adipocyte mitochondria. After briefly summarizing the fundamental aspects of mitochondrial biology, the article describes the protective role of functional mitochondria in white adipocyte and white adipose tissue health and various roles of dysfunctional mitochondria in unhealthy white adipocytes and obesity. Finally, the article emphasizes the importance of enhancing mitochondrial quantity and quality as a therapeutic avenue to correct mitochondrial dysfunction, promote white adipocyte browning, and ultimately improve obesity and its associated metabolic diseases. © 2024 American Physiological Society. Compr Physiol 14:5581‐5640, 2024.

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The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12

Cited by 118 publications

References 53 publications

Itaconate: an emerging determinant of inflammation in activated macrophages

Itaconate: an emerging determinant of inflammation in activated macrophages

Discovery of a novel stereospecific β-hydroxyacyl-CoA lyase/thioesterase shared by three metabolic pathways inMycobacterium tuberculosis

Mitochondrial Function and Dysfunction in White Adipocytes and Therapeutic Implications

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