Abstract
Chaperone-mediated autophagy (CMA) selectively degrades a subset of cytosolic proteins in lysosomes. A potent physiological activator of CMA is nutrient deprivation, a condition in which intracellular triglyceride stores or lipid droplets (LDs) also undergo hydrolysis (lipolysis) to generate free fatty acids for energetic purposes. Here we report that the LD-associated proteins perilipin 2 (PLIN2) and perilipin 3 (PLIN3) are CMA substrates and their degradation through CMA precedes lipolysis. In vivo studies revealed that CMA degradation of PLIN2 and PLIN3 was enhanced during starvation, concurrent with elevated levels of cytosolic adipose triglyceride lipase (ATGL) and macroautophagy proteins on LDs. CMA blockage both in cultured cells and mouse liver or expression of CMA-resistant PLINs leads to reduced association of ATGL and macrolipophagy-related proteins with LDs and the subsequent decrease in lipid oxidation and accumulation of LDs. We propose a role for CMA in LD biology and in the maintenance of lipid homeostasis.
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Acknowledgements
This work was supported by grants from the National Institutes of Health AG021904, AG031782, AG038072, DK098408 and the generous support of Robert and Renée Belfer. We thank B. Patel for performing the electron microscopy, R. Singh for assistance in biochemical lipid assays and the Analytical Imaging Facility for support with live-cell imaging.
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S.K. designed and performed the experiments, analysed and interpreted the data, and contributed to writing the manuscript; A.M.C. coordinated the study, contributed to designing and interpretation of the experiments and to writing the manuscript.
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Integrated supplementary information
Supplementary Figure 1 LAMP-2A-deficient cells accumulate LD.
(a) MitoTracker and MitoTracker CMXRos staining in CTR and L2A(−) cells untreated or treated with OL. Graph: average percentage colocalization between the two fluorophores. n = 4 independent experiments with 40 cells per condition in each experiment. (b) CTR and L2A(−) expressing mtKeima untreated or treated with OL. FCCP is shown as a positive control. Graph: average number/cell. n = 9 fields with 1350 cells per condition from 3 independent experiments. (c) Oil Red O staining in WT and L2AKO liver sections. Graphs: LD number, LD size and percentage of cytosolic area occupied by LD. n = 6 micrographs from 3 animals in each group. (d) LD size for the cells shown in Fig. 1e. n = 7 independent experiments with 40 cells per condition in each experiment. (e,f) DPH staining in CTR and L2A(−) cells untreated or treated with OL, or incubated with serum-supplemented medium (OL > S+) or serum-deprived medium (OL > S−) after OL treatment. Graph: average LD number/cell. n = 5 independent experiments with 40 cells per condition in each experiment. (g) BODIPY 493/503 staining in OL-treated CTR and L2A(−) cells untreated or treated with etomoxir. Graph: average LD number/cell. n = 5 independent experiments with 40 cells per condition in each experiment. (h) BODIPY 493/603 staining in CTR and L2A(−) cells maintained in the indicated conditions. Graph: average LD number/cell. n = 18 fields with 2700 cells per condition from 3 independent experiments. (i) Immunoblot for hLAMP2 in CTR and L2A(−) cells transfected with hL2A. (j) Immunostaining for hLAMP2 in CTR and L2A(−) cells transfected with hL2A and treated with OL. Values are mean ± SEM. Differences are significant for ∗P < 0.05,∗∗P < 0.01,∗∗∗P < 0.001 using Student’s t-test. Uncropped images of blots are shown in Supplementary Fig. 8. Source data is available in Supplementary Table 1.
Supplementary Figure 2 PLIN2 and PLIN3 are CMA substrates.
(a) Immunoblot for indicated proteins in total cell lysates from CTR and L2A(−) cells. Two sets of cells are shown. (b) BODIPY 493/503 staining in control cells untreated or treated with ammonium chloride and leupeptin (NL), lactacystin (Lacta) or MG132. Graph: average LD number/cell. n = 5 independent experiments with 40 cells per condition in each experiment. (c) Immunoblot for indicated proteins in total cell lysates from CTR and L2A(−) cells treated or not with OL and lactacystin (Lacta). n = 2 independent experiments. (d,e) CTR and L2A(−) cells expressing DGN or DGN-FS treated or not with OL and Lacta. Graph: average fluorescence intensity/cell. n = 10 fields with 1500 cells per condition from 3 independent experiments. (f,g) Coimmunostaining for PLIN3 and LAMP1 in CTR and L2A(−) cells treated or not with OL, followed by treatment with lysosomal inhibitors (NL). Top: Colocalized pixels in white. Bottom: Merged image of the boxed area at higher magnification. Graph: percentage colocalization of PLIN3 with LAMP1. n = 5 (L2A(−)) and 6 (CTR) independent experiments with 40 cells per condition in each experiment. (h) Immunoblot for indicated proteins of HOM, CMA+ and CMA− lysosomes isolated from fed or starved (Stv) livers of rat untreated or treated with leupeptin (Leup). These blots contributed to the quantification shown in Fig. 2g. All values are mean ± SEM. Differences are significant for ∗P < 0.05,∗∗P < 0.01,∗∗∗P < 0.001 using Student’s t-test. Uncropped images of blots are shown in Supplementary Fig. 8. Source data is available in Supplementary Table 1.
Supplementary Figure 3 PLIN2 and PLIN3 associate with hsc70.
(a) Coimmunostaining for PLIN3 and hsc70 in CTR and L2A(−) cells treated or not with OL. Colocalized pixels are in white. Boxed areas are shown at higher magnification. Bottom: graph: percentage colocalization of PLIN3 (bottom) with hsc70. n = 5 independent experiments with 40 cells per condition in each experiment. (b) Coimmunostaining for PLIN2 and hsc70 in CTR and L2A(−) cells treated as indicated. Colocalized pixels are in white. Graph: percentage colocalization. n = 4 independent experiments with 40 cells per condition in each experiment. (c,d) Immunoblot for indicated proteins of immunoprecipitates (IP) of hsc70 from total extracts of CTR and L2A(−) cells treated or not with OL. Representative blots of n = 3 independent experiments. (e) Immunoblot for indicated proteins of IP of GAPDH (top) and IkB (bottom) from total extracts of CTR and L2A(−) cells. (f) Immunoblot for indicated proteins of IP of PLIN2 (top) and PLIN3 (bottom) from total extracts of CTR and L2A(−) cells treated with the indicated increasing concentrations of OL. These blots are an extension of those shown in Fig. 3e, f to show the dose-dependence effect. Representative blots of n = 3 (PLIN3) and 4 (PLIN2) independent experiments. Values are mean ± SEM. Differences are significant for ∗P < 0.05,∗∗P < 0.01,∗∗∗P < 0.001 using Student’s t-test. Uncropped images of blots are shown in Supplementary Fig. 8. Source data is available in Supplementary Table 1.
Supplementary Figure 4 Inhibition of PLIN2 degradation by CMA leads to lipid droplet accumulation.
(a) Immunostaining for hsc70 in OL-treated cells expressing WT or MT PLIN2-GFP. Right: 3D-reconstruction of the marked regions of the images shown on left. See also Supplementary Video 1 . (b) Right: Serial Z-sections of the marked region of CTR cells expressing MT PLIN2-GFP shown on left.
Supplementary Figure 5 Altered cytosolic and lysosomal lipolysis in CMA-incompetent cells.
(a) Coimmunostaining for PLIN2 and ATGL in CTR and L2A(−) cells untreated or treated with OL or incubated with serum-supplemented (OL > S+) or serum-deprived (OL > S−) medium after OL treatment. Insets: Higher magnification areas. Right: Images of the same fields with colocalized pixels shown in white. Graph: percentage colocalization of PLIN2 with ATGL. n = 5 independent experiments with 40 cells per condition in each experiment. (b) Costaining for BODIPY493/503 and ATGL in CTR and L2A(−) cells incubated or not in OL > S+ regular or low glucose media. Bottom: Higher magnification areas. Graph: percentage colocalization of BODIPY with ATGL. n = 5 independent experiments with 40 cells per condition in each experiment. (c) Immunoblot for ATGL of homogenates (HOM) and lipid droplets (LD) isolated from starved wild-type (+) or L2A knockout (−) mice livers (these 3 additional blots support the reproducibility of the blot shown in Fig. 6i). (d) BODIPY493/503 staining in CTR and L2A(−) cells untreated or treated with OL, or treated with 3-methyladenine (3MA) or lysosomal inhibitors ammonium chloride and leupeptin (NL). Higher magnification insets and quantification are shown in Fig. 7a. (e) Immunoblot for LC3 of total cell lysates from CTR and L2A(−) cells treated with OL in the presence or absence of 3-methyladenine (3MA). n = 3 independent experiments. (f) Immunostaining for LC3 in OL-treated CTR and L2A(−) cells. Graph: average number of LC3 puncta/cell. n = 6 independent experiments with 30 cells per condition in each experiment. Values are mean ± SEM. Differences are significant for ∗∗P < 0.01,∗∗∗P < 0.001 using Student’s t-test. Uncropped images of blots are shown in Supplementary Fig. 8. Source data is available in Supplementary Table 1.
Supplementary Figure 6 Failure to remove PLINs by CMA alters association of macroautophagy proteins with LD.
(a,b) Costaining for BODIPY 493/503 and the indicated macroautophagy proteins in CTR cells treated or not with OL. Colocalized pixels are in white. Graph: Percentage colocalization with BODIPY. n = 3 independent experiments with 40 cells per condition in each experiment. (c–f) Costaining for BODIPY493/503 and indicated macroautophagy proteins in CTR and L2A(−) cells treated with OL. Right in c: Colocalized pixels of the boxed area at higher magnification. e,f: Colocalized pixels are shown. Graphs: percentage colocalization with BODIPY. n = 6 (d), 7 (e), 3 (f) independent experiments with 30 (d) 40 (e), 10 (f) cells per condition in each experiment. Values are mean ± SEM. Differences are significant for ∗P < 0.05,∗∗P < 0.01,∗∗∗P < 0.001 using Student’s t-test. Source data is available in Supplementary Table 1.
Supplementary Figure 7 Failure to remove PLINs by CMA blocks macrolipophagy.
(a) Live-cell imaging of cells cotransfected with wild-type (WT) or CMA-mutant (MT) PLIN2-GFP and dsRed-LC3 and treated with OL. Sequential frames at 30s intervals are shown. Arrows: LD. See also Supplementary Video 4 . (b) Immunostaining for ATG5 (top) or Beclin1 (bottom) in cells expressing WT or MT PLIN2-GFP treated with OL. Higher magnification show colocalized pixels in white. Graph: percentage colocalization PLIN2-GFP. n = 5 independent experiments with 40 cells per condition in each experiment. (c) Immunostaining for LC3 in OL-treated cells expressing WT or MT PLIN2-GFP. Right: 3D-reconstruction of the images shown on left. See also Supplementary Video 5 . (d) Electron microscopy of CTR or L2A(−) cells maintained in serum-deprived media with or without OL. Several fields are shown. Insets on the right show details of different morphological features previously attributed to macrolipophagy18 and that include: LD (blue arrows; no limiting membrane); where a limiting membrane appears to be forming on the LD surface (yellow arrows); vesicles (putative autolysosomes) containing cargo compatible with lipids (red arrows; limiting membrane) and LD with membranes that originate from their surface toward the core of the LD (green arrows), previously described to correspond to LC3-positive limiting membranes1. Micrographs originate from 3 independent experiments. Values are mean ± SEM. Differences are significant for ∗∗∗P < 0.001 using Student’s t-test. Source data is available in Supplementary Table 1.
Supplementary Figure 8 Images of the uncropped immunoblots with molecular weight markers of the blot data shown in the main and the Supplementary Figures.
Boxes indicate cropped regions. Molecular weight markers are color coded according to the key shown on the bottom right.
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3D-reconstruction of WT or MT PLIN2 and hsc70.
3D-reconstruction of fluorescence stacks of NIH3T3 cells transfected with wild type (WT) or CMA-motif mutated (MT) PLIN2-GFP and immunostained for hsc70. Left: progression from bottom to top. Right: planar rotation. (AVI 5457 kb)
Dynamics of WT or MT PLIN2 in NIH3T3 cells.
Time-lapse microscopy of NIH3T3 cells transfected with wild type (WT) or CMA-motif mutated (MT) PLIN2-GFP. Green channel shown. Arrows point to lipid droplets. (AVI 556 kb)
Dynamics of WT or MT PLIN2 and LAMP1 in NIH3T3 cells.
Time-lapse microscopy of NIH3T3 cells co-transfected with wild type (WT) or CMA-motif mutated (MT) PLIN2-GFP and with LAMP1-RFP. Merged channels are shown. Right shows details at higher magnification. Arrows point to lipid droplets. (AVI 1202 kb)
Dynamics of WT or MT PLIN2 and LC3 in NIH3T3 cells.
Time-lapse microscopy of NIH3T3 cells co-transfected with wild type (WT) or CMA-motif mutated (MT) PLIN2-GFP and with dsRed-LC3. Merged channels are shown. Right shows details at higher magnification. (AVI 624 kb)
3D-reconstruction of WT or MT PLIN2 and LC3.
3D-reconstruction of fluorescence stacks of NIH3T3 cells transfected with wild type (WT) or CMA-motif mutated (MT) PLIN2-GFP and immunostained for LC3. Left: progression from bottom to top. Right: planar rotation. (AVI 9631 kb)
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Kaushik, S., Cuervo, A. Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis. Nat Cell Biol 17, 759–770 (2015). https://doi.org/10.1038/ncb3166
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DOI: https://doi.org/10.1038/ncb3166
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