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The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential

Sandrine Obba1, Zoheir Hizir, Laurent Boyer

  • 1a Inserm U1065 / C3M, Team 2; Cell Death Differentiation Inflammation and Cancer Nice , France.

Autophagy
|June 2, 2015
PubMed

Insights

Colony stimulating factor 1 (CSF1) drives monocyte differentiation via autophagy. The CAMKK2-PRKAA1-ULK1 pathway links CSF1 receptor signaling to P2RY6-mediated autophagy, crucial for this process and potentially CMML therapies.

Area of Science:

  • Cellular biology
  • Immunology
  • Molecular mechanisms

Background:

  • Autophagy is crucial for monocyte differentiation into macrophages, a process mediated by colony stimulating factor 1 (CSF1).
  • The precise molecular pathways connecting CSF1 receptor activation to autophagy induction remain largely unelucidated.

Purpose of the Study:

  • To investigate the molecular mechanisms linking CSF1 receptor engagement to autophagy induction during human monocyte differentiation.
  • To identify the signaling pathway responsible for CSF1-mediated autophagy and its role in monocyte differentiation.

Main Methods:

  • Utilized molecular biology techniques to study the CAMKK2-PRKAA1-ULK1 pathway.
  • Investigated the link between CSF1 receptor, P2RY6, and autophagy.
  • Examined the effects of P2RY6 ligands on primary myeloid cells from chronic myelomonocytic leukemia (CMML) patients.

Main Results:

  • The CAMKK2-PRKAA1-ULK1 pathway is essential for CSF1-induced autophagy and monocyte differentiation.
  • This pathway connects CSF1 receptor signaling to P2RY6-mediated autophagy.
  • UDP and MRS2693 (P2RY6 agonists) partially restored monocyte differentiation in some CMML patient cells by reinducing autophagy.

Conclusions:

  • PRKAA1-mediated autophagy plays a critical role in human monocyte differentiation.
  • The identified signaling network provides insights into CSF1-induced autophagy.
  • Targeting P2RY6-mediated autophagy may offer therapeutic potential for CMML.
Keywords:
ACTB actin, βCAMKK2, calcium/calmodulin-dependent protein kinase kinase 2, βCASP8, caspase 8CFLAR CASP8 and FADD-like apoptosis regulatorCMMLCMML chronic myelomonocytic leukemiaCSF1CSF1 colony stimulating factor 1 (macrophage)CSF1R colony stimulating factor 1 receptorDEFA1 defensin α 1DEFA3 defensin α 3 neutrophil-specificDRS; dorsomorphinEMR1 EGF-like module-containing mucin-like hormone receptor-like 1FADD Fas (TNFRSF6)-associated via death domainG-protein coupled 6ITGAM integrin α MMAP1LC3B/LC3B microtubule-associated protein 1 light chain 3 βP2RY6P2RY6 pyrimidinergic receptor P2YPLC phospholipasePLCB3 phospholipase CPLCG2 phospholipase C gamma 2 (phosphatidylinositol-specific)PRKAA protein kinase AMP-activatedPRKAA1 protein kinase AMP-activated α 1 catalytic subunitPRKAA1/AMPKα1PRKAA2 protein kinase AMP-activated α 2 catalytic subunitPRKAG1 protein kinase AMP-activated gamma 1 noncatalytic subunitRIPK1 receptor (TNFRSF)-interacting serine-threonine kinase 1STK11 serine/threonine kinase 11TFRC transferrin receptorUDP uridine diphosphateULK1 unc-51 like autophagy activating kinase 1WT wild-typeapoptosis-related cysteine peptidaseautophagydifferentiationprimary monocyteβ 3 (phosphatidylinositol-specific)

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