Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Abstract

While the transition metal copper (Cu) is an essential nutrient that is conventionally viewed as a static cofactor within enzyme active sites, a nontraditional role for Cu as a modulator of kinase signaling is emerging. We discovered that Cu is required for the activity of the autophagic kinases ULK1/2 through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt Cu-binding reduced ULK1/2-dependent signaling and autophagosome complex formation. Elevated intracellular Cu levels are associated with starvation induced autophagy and sufficient to enhance ULK1 kinase activity and in turn autophagic flux. The growth and survival of lung tumors driven by KRAS G12D is diminished in the absence of Ctr1 , depends on ULK1 Cu-binding, and is associated with reduced autophagy levels and signaling. These findings suggest a molecular basis for exploiting Cu-chelation therapy to forestall autophagy signaling to limit proliferation and survival in cancer.

RETRACTED: mtROS-mediated Akt/AMPK/mTOR pathway was involved in Copper-induced autophagy and it attenuates Copper-induced apoptosis in RAW264.7 mouse monocytes

“…In the presence of stressful conditions, like OS, malignancy and serum deprivation, autophagy will be triggered for the sake of adapting to structural remodeling induced by the stresses, which is achieved through the synthesis of greater amounts of energy and nutrients, removal of misfolded and long-lived proteins in cells, and the elimination of redundant or injured organelles together with the invasive microorganisms [ 10 ]. It has shown that Cu can induce autophagy [ [11] , [12] , [13] ]. Fang et al [ 14 ] have reported that CuSO 4 promotes autophagy occurrence and ROS exert an important role in autophagy induced by CuSO 4 in duck renal tubular epithelial cells.…”

Copper – a novel stimulator of autophagy

“…Conversely, the authors also found that copper deficiency decreases the formation of autophagy-initiating phagophores, which contain important ULK1/2 downstream targets (Figure 1). Finally, when expressing an ULK1 mutant that lacks the histidine-methionine copper binding sequence, Tsang et al observed reduced ULK1 kinase activity as well as a significantly reduced autophagic flux in response to amino acid deprivation [7]. Altogether, these findings are compatible with the conclusion that copper binding to ULK1/2 is necessary and sufficient to increase autophagic flux.…”

“…In direct agreement with this vison, Tsang et al found that two pro-autophagic kinases, Unc-51 like autophagy activating kinases 1 and 2 (ULK1, ULK2) possess MEK1-like copper-binding sequences [7]. In vitro, ULK1 and 2 do not bind iron or zinc, but copper, which dose-dependently increases their kinase activity.…”

Mammalian copper homeostasis requires retromer-dependent recycling of the high-affinity copper transporter 1

“…Regulated copper homeostasis is fundamental in mammalian cells. Copper is an essential substrate for cell growth and differentiation, a cofactor of many enzymes and has even recently been identified as being necessary for ULK1 and ULK2 signalling, linking it to autophagy activity ( Kim et al, 2008 ; Tsang et al, 2020 ). Therefore, it is unsurprising there are severe adverse effects associated with copper dyshomeostasis.…”