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MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB

Author

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  • Cynthia L. Hsu

    (University of California, San Diego)

  • Elian X. Lee

    (University of California, San Diego)

  • Kara L. Gordon

    (University of California, San Diego)

  • Edwin A. Paz

    (Duke Center for Neurodegeneration and Neurotherapeutics, Duke University School of Medicine)

  • Wen-Chuan Shen

    (Duke Center for Neurodegeneration and Neurotherapeutics, Duke University School of Medicine)

  • Kohta Ohnishi

    (University of California, San Diego)

  • Jill Meisenhelder

    (Salk Institute for Biological Studies)

  • Tony Hunter

    (Salk Institute for Biological Studies)

  • Albert R. La Spada

    (University of California, San Diego
    Duke Center for Neurodegeneration and Neurotherapeutics, Duke University School of Medicine)

Abstract

Autophagy is the major cellular pathway by which macromolecules are degraded, and amino acid depletion powerfully activates autophagy. MAP4K3, or germinal-center kinase-like kinase, is required for robust cell growth in response to amino acids, but the basis for MAP4K3 regulation of cellular metabolic disposition remains unknown. Here we identify MAP4K3 as an amino acid-dependent regulator of autophagy through its phosphorylation of transcription factor EB (TFEB), a transcriptional activator of autophagy, and through amino acid starvation-dependent lysosomal localization of MAP4K3. We document that MAP4K3 physically interacts with TFEB and MAP4K3 inhibition is sufficient for TFEB nuclear localization, target gene transactivation, and autophagy, even when mTORC1 is activated. Moreover, MAP4K3 serine 3 phosphorylation of TFEB is required for TFEB interaction with mTORC1-Rag GTPase-Ragulator complex and TFEB cytosolic sequestration. Our results uncover a role for MAP4K3 in the control of autophagy and reveal MAP4K3 as a central node in nutrient-sensing regulation.

Suggested Citation

  • Cynthia L. Hsu & Elian X. Lee & Kara L. Gordon & Edwin A. Paz & Wen-Chuan Shen & Kohta Ohnishi & Jill Meisenhelder & Tony Hunter & Albert R. La Spada, 2018. "MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03340-7
    DOI: 10.1038/s41467-018-03340-7
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    Cited by:

    1. Anshuman Sewda & A J Agopian & Elizabeth Goldmuntz & Hakon Hakonarson & Bernice E Morrow & Deanne Taylor & Laura E Mitchell & on behalf of the Pediatric Cardiac Genomics Consortium, 2019. "Gene-based genome-wide association studies and meta-analyses of conotruncal heart defects," PLOS ONE, Public Library of Science, vol. 14(7), pages 1-19, July.
    2. Kaushal Asrani & Juhyung Woo & Adrianna A. Mendes & Ethan Schaffer & Thiago Vidotto & Clarence Rachel Villanueva & Kewen Feng & Lia Oliveira & Sanjana Murali & Hans B. Liu & Daniela C. Salles & Brando, 2022. "An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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