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N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation
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N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation
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Journal Article
N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation
2019
Overview
N-myristoyltransferase (NMT) attaches the fatty acid myristate to the N-terminal glycine of proteins to sort them into soluble and membrane-bound fractions. Function of the energy-sensing AMP-activated protein kinase, AMPK, is myristoylation dependent. In rheumatoid arthritis (RA), pathogenic T cells shift glucose away from adenosine tri-phosphate production toward synthetic and proliferative programs, promoting proliferation, cytokine production, and tissue invasion. We found that RA T cells had a defect in NMT1 function, which prevented AMPK activation and enabled unopposed mTORC1 signaling. Lack of the myristate lipid tail disrupted the lysosomal translocation and activation of AMPK. Instead, myristoylation-incompetent RA T cells hyperactivated the mTORC1 pathway and differentiated into pro-inflammatory T
H
1 and T
H
17 helper T cells. In vivo, NMT1 loss caused robust synovial tissue inflammation, whereas forced NMT1 overexpression rescued AMPK activation and suppressed synovitis. Thus, NMT1 has tissue-protective functions by facilitating lysosomal recruitment of AMPK and dampening mTORC1 signaling.
Pathogenic human CD4
+
T cells in rheumatoid arthritis have hyperactivated metabolism. Weyand and colleagues show that this phenotype is associated with less myristoylation of the energy sensor AMPK and dysregulated metabolic sensor mTORC1.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Acyltransferases - immunology
/ Acyltransferases - metabolism
/ Adult
/ AMP
/ AMP-activated protein kinase
/ AMP-Activated Protein Kinases - genetics
/ AMP-Activated Protein Kinases - immunology
/ AMP-Activated Protein Kinases - metabolism
/ Animals
/ Arthritis, Rheumatoid - genetics
/ Arthritis, Rheumatoid - immunology
/ Arthritis, Rheumatoid - metabolism
/ B cells
/ Biomedical and Life Sciences
/ Cyclic AMP-dependent protein kinases
/ Enzyme Activation - immunology
/ Female
/ Glucose
/ Glycine
/ Humans
/ Kinases
/ Male
/ Proteins
/ T cells
