The nuclear cofactor DOR regulates autophagy in mammalian and Drosophila cells.
The regulation of autophagy in metazoans is only partly understood, and there is a need to identify the proteins that control this process. The diabetes- and obesity-regulated gene (DOR), a recently reported nuclear cofactor of thyroid hormone receptors, is expressed abundantly in metabolically active tissues such as muscle. Here, we show that DOR shuttles between the nucleus and the cytoplasm, depending on cellular stress conditions, and re-localizes to autophagosomes on autophagy activation. We demonstrate that DOR interacts physically with autophagic proteins Golgi-associated ATPase enhancer of 16 kDa (GATE16) and microtubule-associated protein 1A/1B-light chain 3. Gain-of-function and loss-of-function studies indicate that DOR stimulates autophagosome formation and accelerates the degradation of stable proteins. CG11347, the DOR Drosophila homologue, has been predicted to interact with the Drosophila Atg8 homologues, which suggests functional conservation in autophagy. Flies lacking CG11347 show reduced autophagy in the fat body during pupal development. All together, our data indicate that DOR regulates autophagosome formation and protein degradation in mammalian and Drosophila cells.
Mauvezin
Caroline
C
Institute for Research in Biomedicine (IRB Barcelona), C/Baldiri Reixac 10, Barcelona 08028, Spain.
Orpinell
Meritxell
M
Francis
Víctor A
VA
Mansilla
Francisco
F
Duran
Jordi
J
Ribas
Vicent
V
Palacín
Manuel
M
Boya
Patricia
P
Teleman
Aurelio A
AA
Zorzano
Antonio
A
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003920:Diabetes Mellitus; D004330:Drosophila / Q000033:anatomy & histology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005216:Fat Body / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D013312:Stress, Physiological
C548146:CG11347 protein, Drosophila; D029721:Drosophila Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D011988:Receptors, Thyroid Hormone