In rheumatoid arthritis (RA), T cells have an altered metabolic profile in which glucose is shifted from glycolysis and ATP production (an energy-conserving programme) to the pentose phosphate pathway and biosynthesis (a cell-building programme). This rerouting of glucose leads to a tissue-invasive and pro-inflammatory phenotype in T cells that is thought to drive chronic inflammation. In a new study, researchers implicate dysfunctional lysosomal recruitment of energy sensor AMP-activated protein kinase (AMPK) in this process.

Credit: Springer Nature Limited

“To coordinate energy supply and proliferative behaviour, cells use AMPK to sense their energy resources,” explains corresponding author Cornelia Weyand. “AMPK is activated when AMP/ATP and ADP/ATP ratios rise and it restores energy balance by switching on catabolic processes to produce ATP and switching off anabolic processes that consume ATP.”

“The counter player of AMPK, the mammalian target of rapamycin (mTOR), integrates growth factor signals with nutrient sensing to promote cellular replication and growth,” says Weyand. “Importantly, these two systems are interconnected: under low-energy conditions, AMPK inactivates mTORC1.” The function of AMPK is dependent on its translocation to the lysosome, which requires N-myristoylation of its β1 and β2 subunits, catalyzed by N-myristoyltransferase (NMT).

In the new study, the researchers detected defective N-myristoylation in CD4+ T cells from patients with RA (hereafter referred to as RA T cells). RA T cells had lower concentrations of NMT1 than T cells from healthy individuals or patients with other autoimmune diseases. This reduced NMT1 abundance was associated with increased T helper 1 (TH1) cell and TH17 cell differentiation in vitro, which could be mimicked by silencing NMT1 in healthy T cells or suppressed by forcing NMT1 overexpression.

“Loss-of-function of NMT1 biased T cells to cause synovial inflammation in a model system of human synovial tissue engrafted into immune-deficient mice,” reports Weyand. “By contrast, gain-of-function of NMT1 in RA T cells was sufficient to suppress synovial inflammation in this model.”

The researchers found that NMT1 deficiency prevented lysosomal recruitment and activation of AMPK, resulting in unrestrained mTORC1 signalling. Administration of an AMPK activator that functions independently of the lysosomal pathway (A769662), but not of metformin (an AMPK activator that functions through the lysosomal pathway), inhibited tissue inflammation in the human-synovium chimera model, and had comparable effects to mTORC1 inhibitor rapamycin.

NMT1 deficiency prevented lysosomal recruitment and activation of AMPK

“We have essentially identified a new therapeutic target and we are planning clinical trials that bring this strategy from the bench to the bedside,” concludes Weyand.