Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 15, Pages 10703-10714Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.414771
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Funding
- National Institutes of Health from the United States Public Health Service [N01-HV28180, HHS-N268201000032c]
- Johns Hopkins Institute for Cell Engineering and Dean's Research Funding
- American Heart Association Predoctoral Fellowship [10PRE4160120]
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Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that mediates adaptive responses to hypoxia. We demonstrate that lysosomal degradation of the HIF-1 alpha subunit by chaperone-mediated autophagy (CMA) is a major regulator of HIF-1 activity. Pharmacological inhibitors of lysosomal degradation, such as bafilomycin and chloroquine, increased HIF-1 alpha levels and HIF-1 activity, whereas activators of chaper-one-mediated autophagy, including 6-aminonicotinamide and nutrient starvation, decreased HIF-1 alpha levels and HIF-1 activity. In contrast, macroautophagy inhibitors did not increase HIF-1 activity. Transcription factor EB, a master regulator of lysosomal biogenesis, also negatively regulated HIF-1 activity. HIF-1 alpha interacts with HSC70 and LAMP2A, which are core components of the CMA machinery. Overexpression of HSC70 or LAMP2A decreased HIF-1 alpha protein levels, whereas knockdown had the opposite effect. Finally, hypoxia increased the transcription of genes involved in CMA and lysosomal biogenesis in cancer cells. Thus, pharmacological and genetic approaches identify CMA as a major regulator of HIF-1 activity and identify interplay between autophagy and the response to hypoxia.
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