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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Hsu CL,Lee EX,Gordon KL,Paz EA,Shen WC,Ohnishi K,Meisenhelder J,Hunter T,La Spada ARdoi
10.1038/s41467-018-03340-7subject
Has Abstractpub_date
2018-03-05 00:00:00pages
942issue
1issn
2041-1723pii
10.1038/s41467-018-03340-7journal_volume
9pub_type
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