Abstract
Autophagy is an essential eukaryotic pathway requiring tight regulation to maintain homeostasis and preclude disease. Using yeast and mammalian cells, we report a conserved mechanism of autophagy regulation by RNA helicase RCK family members in association with the decapping enzyme Dcp2. Under nutrient-replete conditions, Dcp2 undergoes TOR-dependent phosphorylation and associates with RCK members to form a complex with autophagy-related (ATG) mRNA transcripts, leading to decapping, degradation and autophagy suppression. Simultaneous with the induction of ATG mRNA synthesis, starvation reverses the process, facilitating ATG mRNA accumulation and autophagy induction. This conserved post-transcriptional mechanism modulates fungal virulence and the mammalian inflammasome, the latter providing mechanistic insight into autoimmunity reported in a patient with a PIK3CD/p110δ gain-of-function mutation. We propose a dynamic model wherein RCK family members, in conjunction with Dcp2, function in controlling ATG mRNA stability to govern autophagy, which in turn modulates vital cellular processes affecting inflammation and microbial pathogenesis.
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Acknowledgements
The authors thank J. Kim (University of Michigan, National Institutes of Health grant GM088565) for providing the RBP knockout library and V. Nagarajan (Genomic Technologies Section, Research Technologies Branch, NIAID, NIH) for genomic analysis. This work was financially supported, in part, by the Intramural Research Program of the NIH, NIAID, NICHD and by National Institutes of Health grant GM053396 (to D.J.K.).
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G.H.: experimental work, project planning, data analysis, writing; T.M.: experimental work, project planning, data analysis, writing; A.B.: experimental work, project planning, data analysis, writing; Y-D.P.: experimental work, project planning, data analysis, writing; J.Q.: experimental work, data analysis, writing; A.V.: experimental work, data analysis, writing; N.Z.: experimental work, data analysis, writing; S.R.W.: experimental work, data analysis, writing; N.H.B.: experimental work, data analysis, writing; T.G.M.: experimental work, data analysis, writing; R.J.M.: data analysis, project planning, writing; J.H.K.: data analysis, project planning, writing, editing; G.U.: experimental work, data analysis, protocol preparation, writing, editing; D.J.K.: project planning, data analysis, writing, editing; P.R.W.: project planning, data analysis, writing, editing.
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Supplementary Figure 7 RCK Member Dhh1 is a Post-transcriptional Repressor of Autophagy in Yeast.
(a,b) Dhh1 represses the expression of ATG genes in nutrient-replete conditions. Wild-type (WT; WLY176) and dhh1Δ cells (YAB269) were grown in rich medium (a), then shifted to nitrogen starvation for 1 h (b). Total RNA was extracted and analysed as in Fig. 1a. Error bars: standard deviation (SD). (a) n = 5 independent experiments except n = 3 for ATG9, 32,34; n = 4 for ATG2 and n = 6 for n = 5 for ATG1,7,8. (b) n = 3 independent experiments except n = 2 for ATG4 in WT cells. Student’s t-test, ∗p < 0.05,∗∗∗p < 0.001. (c–e) Mild overexpression of DHH1 modestly represses autophagy. WT (YAB281) and OE DHH1 cells (YAB282) were grown in YPGal medium (+N) until mid-log phase, then starved for nitrogen (−N) for 5 h (c,d) or 1 h (e). (c) Protein extracts were analysed by western blot. (d) Pho8Δ60 activity was normalized to that of WT cells (set to 100%). Error bars: SD, n = 4 independent experiments. Student’s t-test, ∗∗p < 0.01. (e) Total RNA was extracted and the mRNA levels were quantified by RT-qPCR. The mRNA level of ATG8 was normalized to that in WT cells in rich conditions (set to 1). Error bars: SD, n = 4 independent experiments. Student’ t-test, NS > 0.05. (f) Dcp2 represses autophagy. WT (YTS158) and dcp2-7Δ cells were grown in YPD at 24 °C until early log-phase, then shifted to 38.5 °C for 1 h and starved for 3 h at the same temperature. Pho8Δ60 activity was normalized to that of WT cells (set to 100%). Error bars: SD, n = 5 independent experiments. Student’s t-test, ∗∗∗p < 0.001. (g) Dcp2 represses the expression of Atg1 and Atg9. WT and dcp2-7Δ cells were grown in rich medium until early-log phase. Cells were shifted to 38.5 °C for 1 h then starved. Protein extracts were analysed by western blot. (h) WT (BY4742) and dcp2-7Δ cells were grown in rich medium until early log phase. Cells were then shifted to 38.5 °C for 1 h then starved for 1 h. The mRNA level of individual ATG genes was normalized to the mRNA level of the corresponding gene in WT cells (set to 1). Error bars: SD, n = 3 independent experiments.
Supplementary Figure 8 The RCK Fungal Homolog Vad1 Plays a Role in Decapping and Degradation of Autophagy-related Transcripts
(a) Northern blots of RNA from the indicated strains were hybridized with fragments of the indicated genes. (b) Wild-type fungal cells overexpressing VAD1 from an ACTIN promoter (OE-1, 2) or containing empty vector alone (EV-1, 2) were induced for autophagy by starvation for 1 h followed by northern blot analysis. (c) The indicated strains were observed by DIC for the presence of autophagic bodies (ABs) and quantified in n = 3 independent experiments of 200 cells each by DIC + / − SD. Student’s t-test, ∗∗∗p < 0.001. (d) RNA from WT (left panel) or vad1D mutant mid-log phase strains (right panel) was subjected to either northern blot (hybridized with a fragment of ATG8) and ratios of signal by densitometry to rRNA plotted over time (top panels) or ATG8 was assayed by quantitative RT–PCR normalized to actin (bottom panels) slope: WT versus vad1D p < 0.001. (e) The indicated strains expressing a GFP-Atg8 fusion protein containing either the native or heterologous 3’UTR (EF1a) under the indicated conditions were incubated with phenylmethanesulfonylfluoride for 30 min and observed by DIC microscopy for the presence of autophagic bodies (arrows). Scale bar = 2 μm. Representative image from n = 50 cells.
Supplementary Figure 9 Phosphorylation of TOR-Dependent Sites S614 and S617 Mediates Decapping and Degradation of ATG8 Transcripts, Related to Fig. 4.
(a) Yeast cells under the indicated conditions expressing either WT Dcp2 or an equivalent protein containing either an S > D mutation or S > A mutation at positions S614 and S617 were assayed for decapping of ATG8 transcripts over 30 min by a PCR assay and visualized by ethidium bromide as in Fig. 3b. (b) Decapping assay: Densitometry of n = 3 independent assays Dcp2 containing an S > D mutation or S > A mutation at a single position S614 or S617 were assayed for degradation as in Fig. 4b. Degradation (c) and Decapping (d) assays conducted on yeast cells expressing WT or Dcp2 with single mutations; decapping assay conducted as in Supplementary Fig. 3a and B. All experiments the results of n = 3 independent assays + / − SD. Student’s t-test, ∗p < 0.05,∗∗p < 0.01,∗∗∗p < 0.001,∗∗∗∗p < 0.0001.
Supplementary Figure 10 Phosphorylation of TOR-Dependent Sites S614 and S617 Mediate Decapping of ATG5 T ranscripts, Related to Fig. 4.
(a) Yeast cells under the indicated conditions expressing either WT Dcp2 or an equivalent protein containing either the S > D mutation or S > A mutation at positions S614 and S617 were assayed for decapping of ATG5 transcripts over 30 min by a PCR assay and visualized by ethidium bromide as in Fig. 3b. (b) Densitometry of n = 3 independent decapping assays performed as in Supplementary Fig. 3a. Bars + / − SD; Student’s t-test, ∗p < 0.05,∗∗p < 0.01,∗∗∗p < 0.001.
Supplementary Figure 11 ATG8 and ATG5 Transcripts Demonstrate Robust Translational Efficiency and Induction under Starvation Conditions, related to Figs 2 and 4.
(a) Left panels: Indicated gene transcripts were localized using multiple Cy3-labelled oligonucleotide probes by single mRNA-sensitivity FISH (ATG8-Cy3, ATG5-Cy3) and P-bodies localized by a Vad1-GFP fusion protein. White arrows correspond to P-bodies, red arrows to the indicated transcripts. Right panels: Quantification of mid-log (Glucose +) or starvation conditions (Glucose −) of the indicated fluorescent transcript puncta, Vad1-GFP labelled P-bodies (Vad1) and co-localized puncta on deconvolved images of 20 cells. Student’s t-test, ∗∗∗∗ indicates p < 0.0001. Scale bar = 4 μm. (b) Sucrose gradient sedimentation polysome profiles of extracts from C. neoformans cells under mid-log or starvation conditions. Results of polysome profile quantification of the indicated mRNA are shown below the corresponding sucrose fractions. Corresponding ribonuclear protein (RNP) 40S, 60/80S and polysome fractions as indicated. Error bars indicate the standard deviation of n = 3 independent experiments + / − SD.
Supplementary Figure 12 The RCK Mammalian Homolog DDX6 is a Suppressor of Autophagy in Primary Embryonic Stem Cells, Related to Fig. 5.
(a) Schematic representation of DDX6 WT and two independent DDX6 gene trap insertion clones. (b) Decapping assay: The presence of capped LC3 transcripts was assayed in DDX6 WT, DDX6 clone #1 (DDX6+/−#1), and DDX6 clone #2 (DDX6+/−#2) by the method of Fig. 3 at the indicated times after transcriptional suppression. (c) Degradation assay: Quantification of LC3 transcripts of the indicated cells after transcriptional suppression in n = 3 independent experiments normalized to each respective time zero + / − SD. Student’s t-test, ∗p < 0.05;∗∗p < 0.01.
Supplementary Figure 13 The Mammalian Dcp2 Homolog Is Phosphorylated by MTOR, Related to Fig. 5.
(a) Schematic of the identification of phosphorylated Ser249 of DCP2 by mass spectroscopy. The peptides are represented by green lines and the phosphorylation site is indicated in purple. (b) Differential phosphorylation of DCP2 after treatment with rapamcyin assayed by targeted ion mass spectrometry. (c) SDS-PAGE of recombinant DCP2-MBP fusion protein purified by amylose-agarose affinity chromatography. (d) Ex vivo phosphorylation of DCP2 by MTOR. MTOR was immunoprecipitated from HeLa cells using an anti-MTOR antibody, washed, then incubated with 100 ng DCP2-MBP at 30 °C for the indicated times, and subjected to western blot using a rabbit DCP2-pSer249 affinity-purified antibody. Lower panel, density quantification of pSer249 in n = 3 independent experiments. Bar + / − SD. (e) DCP2-MBP phosphorylated with MTOR for 20 min as in in Supplementary Fig. 3d, then subjected to treatment (+) or no treatment (−) with calf intestinal alkaline phosphatase (CIAP) before western blot using antigen-purified anti-DCP2-pSer249 antibody.
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Hu, G., McQuiston, T., Bernard, A. et al. A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy. Nat Cell Biol 17, 930–942 (2015). https://doi.org/10.1038/ncb3189
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DOI: https://doi.org/10.1038/ncb3189
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