Autophagy is induced during differentiation of human monocytes into macrophages that is mediated by CSF1/CSF-1/M-CSF (colony stimulating factor 1 [macrophage]). However, little is known about the molecular mechanisms that link CSF1 receptor engagement to the induction of autophagy. Here we show that the CAMKK2-PRKAA1-ULK1 pathway is required for CSF1-induced autophagy and human monocyte differentiation. We reveal that this pathway links P2RY6 to the induction of autophagy, and we decipher the signaling network that links the CSF1 receptor to P2RY6-mediated autophagy and monocyte differentiation. In addition, we show that the physiological P2RY6 ligand UDP and the specific P2RY6 agonist MRS2693 can restore normal monocyte differentiation through reinduction of autophagy in primary myeloid cells from some but not all chronic myelomonocytic leukemia (CMML) patients. Collectively, our findings highlight an essential role for PRKAA1-mediated autophagy during differentiation of human monocytes and pave the way for future therapeutic interventions for CMML.
Keywords: ACTB actin, β; CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2, β; CASP8, caspase 8; CFLAR CASP8 and FADD-like apoptosis regulator; CMML; CMML chronic myelomonocytic leukemia; CSF1; CSF1 colony stimulating factor 1 (macrophage); CSF1R colony stimulating factor 1 receptor; DEFA1 defensin α 1; DEFA3 defensin α 3 neutrophil-specific; DRS; dorsomorphin; EMR1 EGF-like module-containing mucin-like hormone receptor-like 1; FADD Fas (TNFRSF6)-associated via death domain; G-protein coupled 6; ITGAM integrin α M; MAP1LC3B/LC3B microtubule-associated protein 1 light chain 3 β; P2RY6; P2RY6 pyrimidinergic receptor P2Y; PLC phospholipase; PLCB3 phospholipase C; PLCG2 phospholipase C gamma 2 (phosphatidylinositol-specific); PRKAA protein kinase AMP-activated; PRKAA1 protein kinase AMP-activated α 1 catalytic subunit; PRKAA1/AMPKα1; PRKAA2 protein kinase AMP-activated α 2 catalytic subunit; PRKAG1 protein kinase AMP-activated gamma 1 noncatalytic subunit; RIPK1 receptor (TNFRSF)-interacting serine-threonine kinase 1; STK11 serine/threonine kinase 11; TFRC transferrin receptor; UDP uridine diphosphate; ULK1 unc-51 like autophagy activating kinase 1; WT wild-type; apoptosis-related cysteine peptidase; autophagy; differentiation; primary monocyte; β 3 (phosphatidylinositol-specific).