The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism.
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.
Department of Laboratory Medicine, Medical University of Vienna, A-1090, Austria. arvand.haschemi@meduniwien.ac.at
Arvand
A
Haschemi
Paul
P
Kosma
Lars
L
Gille
Charles R
CR
Evans
Charles F
CF
Burant
Philipp
P
Starkl
Bernhard
B
Knapp
Robert
R
Haas
Johannes A
JA
Schmid
Christoph
C
Jandl
Shahzada
S
Amir
Gert
G
Lubec
Jaehong
J
Park
Harald
H
Esterbauer
Martin
M
Bilban
Leonardo
L
Brizuela
J Andrew
JA
Pospisilik
Leo E
LE
Otterbein
Oswald
O
Wagner
D000595:Amino Acid Sequence; D000818:Animals; D050260:Carbohydrate Metabolism; D002460:Cell Line; D016764:Cell Polarity; D004311:Double-Blind Method; D015536:Down-Regulation; D019446:Endotoxemia / Q000201:enzymology / Q000276:immunology; D004734:Energy Metabolism; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D015850:Interleukin-6; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D017853:Phosphotransferases (Alcohol Group Acceptor); C404793:SHPK protein, human; D005947:Glucose