DAGL-Beta Functions as a PUFA-Specific Triacylglycerol Lipase in Macrophages
- Cell Chem Biol. 2020 Mar 19;27(3):314-321.e5. doi: 10.1016/j.chembiol.2020.01.005.
- 1. Department of Chemistry, University of Virginia, McCormick Road, PO Box 400319, Charlottesville, VA 22904, USA.
- 2. Department of Chemistry, University of Virginia, McCormick Road, PO Box 400319, Charlottesville, VA 22904, USA; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA; University of Virginia Cancer Center, University of Virginia, Charlottesville, VA 22903, USA. Electronic address: [email protected].
Here, we apply quantitative chemical proteomics and untargeted lipidomics to assign a polyunsaturated fatty acid (PUFA)-specific triacylglycerol (TAG) Lipase activity for diacylglycerol lipase-beta (DAGLβ) in macrophages. We demonstrate that DAGLβ but not DAGLα is expressed and active in bone marrow-derived macrophages (BMDMs) as determined by activity-based protein profiling analysis of SILAC BMDMs. Genetic disruption of DAGLβ resulted in accumulation of cellular TAGs composed of PUFA but not saturated/low unsaturated fatty acid counterparts, which is recapitulated in wild-type macrophages treated with a DAGLβ-selective inhibitor. Biochemical assays with synthetic substrates confirm PUFA-TAGs as authentic DAGLβ substrates. In summary, our findings identify DAGLβ as a PUFA-specific TAG Lipase in primary macrophages.