Hsu, Cynthia L. University of California
Lee, Elian X. University of California
Gordon, Kara L. University of California
Paz, Edwin A. Duke University
Shen, Wen-Chuan Duke University
Ohnishi, Kohta University of California Tokushima University Educator and Researcher Directory
Meisenhelder, Jill Salk Institute for Biological Studies
Hunter, Tony Salk Institute for Biological Studies
La Spada, Albert R. University of California|Duke University
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.
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