N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation

Zhenke Wen, Ke Jin, Yi Shen, Zhen Yang, Yinyin Li, Bowen Wu, Lu Tian, Stanford Shoor, Niall E. Roche, Jorg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)313-325
Number of pages13
JournalNature immunology
Volume20
Issue number3
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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