The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML
Open accessAbstract
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.
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PLCG2 acts broadly to transduce signals from many immune receptors independent of TREM2.
“Furthermore, PLCG2 acts broadly to transduce signals from many immune receptors independent of TREM2 5,18,19 .”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [19]
The section on PLCG2 downstream of the CSF1 receptor reports that PLCG2 acts in CSF1R signaling during human monocyte differentiation. That supports a role outside the TREM2 context, but the paper does not establish that PLCG2 transduces signals from many immune receptors or test TREM2 independence. (LLM, conf=0.84)
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Guidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996 · cited 1× · see citing works
“Flow cytometry The monocyte differentiation, the cell surface expression of P2RY6 and autophagy were studied by flow cytometry.(44) To analyze the macrophagic differentiation of monocytes, cells were washed with ice-cold phosphate-buffered saline (PBS, Life Technologies, 14190169), and incubated at 4 C for 10 min in P…”
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“Nevertheless, the data presented herein deciphers the signaling pathways involved in CSF1-mediated induction of autophagy and monocyte differentiation, as well as paves a new research avenue for future therapeutic interventions through PRKAA reactivation in the context of CMML. Patients were newly diagnosed or had pre…”
BackgroundInfluentialThe machinery of macroautophagy
Feng, Y., He, D., Yao, Z., & Klionsky, D. J. (2014) · Cell Research · doi:10.1038/cr.2013.168 · Cited by 2,083 · see citing works
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
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“Blocking of either Src family kinases (78) or PLCγ2 directly showed it was required downstream of M-CSF signaling to facilitate human monocyte differentiation (79).”
BackgroundTsai, A. P., Dong, C., Lin, P. B.-C., Oblak, A. L., Viana Di Prisco, G., Wang, N., Hajicek, N., Carr, A. J., Lendy, E. K., Hahn, O., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.08.008 · Cited by 71 · see citing works
- Authors
- Obba, S., Hizir, Z., Boyer, L., Selimoglu-Buet, D., Pfeifer, A., Michel, G., Hamouda, M.-A., Gonçalvès, D., Cerezo, M., Marchetti, S., Rocchi, S., Droin, N., Cluzeau, T., Robert, G., Luciano, F., Robaye, B., Foretz, M., Viollet, B., Legros, L., Solary, E., Auberger, P., & Jacquel, A.
- Affiliations
- Inserm (FR)
- Inserm U1009 / Institute Gustave Roussy, Team 3; Normal and Pathological Hematopoiesis; Paris, France
- Inserm U1065 / C3M, Team 1; Biology and Pathology of Melanocyte Cells; Nice, France
- Inserm U1065 / C3M, Team 2; Cell Death Differentiation Inflammation and Cancer Nice, France
- Université Libre de Bruxelles (BE)
- Centre National de la Recherche Scientifique (FR)
- Inserm U1016; Institute Cochin; Paris, France
- Centre Hospitalier Universitaire de Nice (FR)
- Corresponding author
- Auberger, Patrick
- ORCID
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2015-07-03
- Volume
- 11
- Issue
- 7
- Pages
- 1114-1129
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC4590592
- OpenAlex
- W2139175045
- Cited by
- 100
- References
- 8
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 11 · 2023: 11 · 2022: 10 · 2021: 9 · 2020: 11 · 2019: 12 · 2018: 11 · 2017: 11 · 2016: 6 · 2015: 3
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ORBi (University of Liège) (submittedVersion, other-oa)
- HAL (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-LABX-0028)
- Institut National de la Santé et de la Recherche Médicale (ANR-11-LABX-0028-01)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- PRKAA1, AMPKα1, CSF-1 receptor, monocyte differentiation, macrophage differentiation, CAMKK2, ULK1, UDP, chronic myelomonocytic leukemia, myeloid cells
- MeSH terms
- Animals, Autophagy, Cell Differentiation, Enzyme Activation, Humans, Leukemia, Myeloid, Mice, Inbred C57BL, Models, Biological, Monocytes, Uridine Diphosphate, Signal Transduction, Macrophage Colony-Stimulating Factor, Receptors, Purinergic P2, Cell Line, Tumor, Phospholipase C gamma, Calcium-Calmodulin-Dependent Protein Kinase Kinase, AMP-Activated Protein Kinases
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