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Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs

Nature Cell Biology volume 16, pages 1202–1214 (2014)Cite this article

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Abstract

Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A–HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes through Foxk–Sin3-mediated transcriptional control.

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Figure 1: Identification of Foxk1 as a component of a Sin3A complex.
Figure 2: Genome-wide identification of Foxk1-binding sites at promoters and enhancers.
Figure 3: Foxk1 represses transcription of genes associated with induction of atrophy and autophagy initiation.
Figure 4: Nuclear import and export of Foxk1 is mTOR- and CRM1-dependent, respectively.
Figure 5: Starvation, through mTOR inhibition, signals the removal of Foxk1 from chromatin.
Figure 6: Foxk1 and Foxo3 are recruited to the same atrophy and autophagy genes.
Figure 7: Foxk–Sin3A complexes suppress autophagic flux in nutrient-rich conditions.
Figure 8: Model illustrating a role for Foxk1 repression of autophagy and atrophy induction.

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Acknowledgements

We thank W. Lane for mass spectrometric analysis; A. Heguy, E. Venturini and O. Aminova of the New York University Langone Medical Center (NYULMC) Genome Technology Center for ChIP-seq and RNA-seq library sequencing; F. Liang, C. Petzold and K. Dancel of the NYULMC OCS Microscopy Core for the preparation of samples and imaging for TEM; D. Garry (University of Minnesota, USA) for Foxk1 cDNA; Y. Zhang (Harvard Medical School, USA), D. Reinberg (New York University, USA), E. Benevolenskaya (University of Illinois at Chicago, USA) and A. Brunet (Stanford University, USA) for their generous gifts of antibodies. This work used computing resources at the High Performance Computing Facility of the NYULMC Center for Health Informatics and Bioinformatics. This work was supported by NIH grants 2R01CA077245-16 and 2R01GM067132-09A1 to B.D.D. and F30AG040894 to C.J.B.

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Authors and Affiliations

  1. Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA

    Christopher John Bowman & Brian David Dynlacht

  2. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA

    Donald E. Ayer

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Contributions

C.J.B. performed the experiments and bioinformatics analyses. D.E.A. provided Sin3A and Sds3 antibodies. C.J.B. and B.D.D. conceived the project, designed the experiments, analysed the data and wrote the manuscript. All authors reviewed and approved the manuscript.

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Correspondence to Brian David Dynlacht.

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Integrated supplementary information

Supplementary Figure 1 Foxk1 interacts with Sin3A, but not Sin3B, complexes in a DNA-independent manner.

Immunoprecipitates from myoblast nuclear fractions were incubated with and washed with 100 μg/mL ethidium bromide (EtBr) to prevent bridging of proteins by DNA.

Supplementary Figure 2 Foxk1 is recruited to forkhead motifs at promoters and enhancers.

(a) siRNA-mediated depletion of Foxk1 against two distinct target sequences showed significant reductions in Foxk1 recruitment to Foxk1-bound loci. Tnnc1 and Ttn are negative control loci. (b) Co-enrichment of ETS, Runx1, Sox, CREB1, and CCAAT-box motifs at Foxk1 peaks. (c) Single-nucleotide polymorphisms (SNP, red) in functional forkhead motifs abrogate Foxk1 binding. Sequences from our ChIP-seq experiments, which were derived from C2C12 myoblasts of the murine C3H strain, were compared to the reference mm9 assembly, which is sequenced from the C57/BL6 strain. A handful of promoters with a homozygous SNP (colored in red) in the forkhead motif were selected for Foxk1 binding at those loci in myoblasts isolated from either a C3H or C57/BL6 strain. The Tef promoter had an unaltered motif in either strain and retains robust Foxk1 binding, but the promoters of Atpbd4, Bbc3, and Usp48 showed minimal Foxk1 binding due to the presence of an altered forkhead motif. Atp6a1l, negative control region not bound by Foxk1. (d) Foxk1 localized to both promoter and enhancer regions, and Foxk1 recruited Sin3A only to promoters. Data represent mean + SEM from n = three independent experiments. siNS, control knock-down.

Supplementary Figure 3 Foxk1 and Foxk2 redundantly, yet independently, repress autophagy.

(a) Starvation induces the removal of Foxk2 from chromatin at the promoters of autophagy genes and Fbxo32. (b) Foxk2 is transported from the nucleus to the cytoplasm during starvation. (c) Control (siNS) cells or cells depleted of either Foxk1 or Foxk2 were grown in nutrient-rich or starvation medium in the presence or absence of chloroquine (CQ) for 90 min. LC3 and α-tubulin immunoblots correspond to the same gels. Data are presented as mean + SEM from n = three independent experiments. siNS, control knock-down.

Supplementary Figure 4 Foxk1 depletion deregulates autophagy genes.

(a) RNA-seq of non-starved, starved, and Foxk1-depleted myoblasts. siNS, control knock-down. (b) Confirmatory Foxk1 knockdown shows deregulation of autophagy genes using a different siRNA than that used in Fig. 3e. Data represent mean + SEM from n = three independent experiments. siNS, control knock-down.

Supplementary Figure 5 Foxk1 is a phospho-protein whose levels are not reduced during starvation.

(a) Whole cell lysates from cells starved for the indicated times. Quantification from three independent experiments is shown at right. Data are presented as mean + SEM from n = three independent experiments (two-tailed t-test). (b) Foxk1 was dephosphorylated with λ protein phosphatase, and inhibition of phosphatase activity prevented Foxk1 dephosphorylation. De-phosphorylated Foxk1 retained its interaction with Sin3A. Foxk1 immunoprecipitates from myoblast nuclear and cytoplasmic extracts were treated with λ protein phosphatase with or without phosphatase inhibitors, washed, and analyzed by SDS-PAGE and immunoblotting.

Supplementary Figure 6 Starvation leads to histone hyper-acetylation and chromatin de-compaction at sites previously bound by Foxk1-Sin3A complexes.

(a,b) qChIP shows that loss of Foxk1 and Sin3A is associated with (a) a reduction in H4 levels and (b) increased acetylation of H4 at autophagy genes during starvation. Corresponding IgG controls are shown in Fig. 5a. Data represent n = three independent biological replicates from separate dishes and lysate preparations and are presented as mean + SEM. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; NS, not significant (two-tailed t-test).

Supplementary Figure 7 Foxk1 loss increased the number and size of autophagic vacuoles.

Autophagic vacuoles (AV, white arrows) in control siNS knock-down cells are generally 500–600 nm in size and contain cytoplasmic materials such as mitochondria (black arrowheads), endoplasmic reticulum, and electron-dense ribosomes. Foxk1-depleted cells exhibit an increased number of multi-lamellar bodies (white arrowheads) and AVs. The AVs contain an abundance of degrading electron-dense ribosomes and membranes, which are likely to come from mitochondria and endoplasmic reticulum. Bar, 1 μm.

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Bowman, C., Ayer, D. & Dynlacht, B. Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs. Nat Cell Biol 16, 1202–1214 (2014). https://doi.org/10.1038/ncb3062

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