biostudies-literatureWen ZBLRD VANIA NIH HHSNIAID NIH HHSNHLBI NIH HHSNIAMS NIH HHS313-325https://www.ebi.ac.uk/biostudies/studies/S-EPMC6396296biostudies-literatureUnknown20(3)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 TH1 and TH17 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.Nature immunologyN-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation.PMC6396296R01 HL142068R01 AG045779U19 AI057266R01 AR042527R01 HL117913I01 BX001669R01 AI108891P01 HL129941R01 AI108906Yang ZLi YTian LWeyand CMWen ZWu BShen YShoor SJin KRoche NEGoronzy JJfalseN-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation.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 TH1 and TH17 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.2019-01-01T00:00:00Z2019 Mar2024-11-20T15:32:19.015Z2019-08-07T07:03:22ZS-EPMC63962963071891310.1038/s41590-018-0296-7