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PMID:22682222

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Citation

Haschemi, A, Kosma, P, Gille, L, Evans, CR, Burant, CF, Starkl, P, Knapp, B, Haas, R, Schmid, JA, Jandl, C, Amir, S, Lubec, G, Park, J, Esterbauer, H, Bilban, M, Brizuela, L, Pospisilik, JA, Otterbein, LE and Wagner, O (2012) The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab. 15:813-26

Abstract

Immune cells are somewhat unique in that activation responses can alter quantitative phenotypes upwards of 100,000-fold. To date little is known about the metabolic adaptations necessary to mount such dramatic phenotypic shifts. Screening for novel regulators of macrophage activation, we found nonprotein kinases of glucose metabolism among the most enriched classes of candidate immune modulators. We find that one of these, the carbohydrate kinase-like protein CARKL, is rapidly downregulated in vitro and in vivo upon LPS stimulation in both mice and humans. Interestingly, CARKL catalyzes an orphan reaction in the pentose phosphate pathway, refocusing cellular metabolism to a high-redox state upon physiological or artificial downregulation. We find that CARKL-dependent metabolic reprogramming is required for proper M1- and M2-like macrophage polarization and uncover a rate-limiting requirement for appropriate glucose flux in macrophage polarization.

Links

PubMed PMC3370649 Online version:10.1016/j.cmet.2012.04.023

Keywords

Amino Acid Sequence; Animals; Carbohydrate Metabolism; Cell Line; Cell Polarity; Double-Blind Method; Down-Regulation; Endotoxemia/enzymology; Endotoxemia/immunology; Energy Metabolism; Gene Expression Regulation, Enzymologic; Glucose/metabolism; Humans; Interleukin-6/genetics; Interleukin-6/metabolism; Interleukin-6/secretion; Lipopolysaccharides/pharmacology; Macrophages/enzymology; Macrophages/immunology; Macrophages/metabolism; Macrophages/physiology; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Phenotype; Phosphotransferases (Alcohol Group Acceptor)/chemistry; Phosphotransferases (Alcohol Group Acceptor)/genetics; Phosphotransferases (Alcohol Group Acceptor)/metabolism; Protein Structure, Tertiary; Receptors, Immunologic/genetics; Receptors, Immunologic/metabolism; Transcription Factors/chemistry; Transcription Factors/genetics; Transcription Factors/metabolism; Tumor Necrosis Factor-alpha/genetics; Tumor Necrosis Factor-alpha/metabolism; Tumor Necrosis Factor-alpha/secretion

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SHPK

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SHPK

involved_in

GO:0005975: carbohydrate metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHPK

involved_in

GO:0009052: pentose-phosphate shunt, non-oxidative branch

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHPK

involved_in

GO:0050727: regulation of inflammatory response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHPK

involved_in

GO:0043030: regulation of macrophage activation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHPK

involved_in

GO:0071353: cellular response to interleukin-4

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHPK

involved_in

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHPK

enables

GO:0050277: sedoheptulokinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SHPK

involved_in

GO:0035963: cellular response to interleukin-13

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SHPK

involved_in

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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