STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy

Joao Vasco Ferreira, Hugo Fofo, Eloy Bejarano, Carla Figueira Bento, Jose S. Ramalho, Henrique Girao, Paulo Pereira

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

The transcription factor HI F1 is mostly regulated by the oxygen-dependent proteasomal degradation of the labile subunit HI F1A. Recent data showed degradation of HI F1A in the lysosome through chaperone-mediated autophagy (CMA). However the molecular mechanism involved has not been elucidated. This study shows that the KFER Q-like motif, that has been identified in all CMA substrates, is required to mediate the interaction between HI F1A and the chaperone HSPA8. Moreover, mutations in the KFER Q-like motif of HI F1A preclude the interaction with the CMA receptor LAMP2A, thus inhibiting its lysosomal degradation. Importantly, we show for the first time that the ubiquitin ligase STUB1 is required for degradation of HI F1A in the lysosome by CMA. Indeed, mutations in STUB1 that inhibit either the ubiquitin ligase activity or its ability to bind to HSPA8, both prevent degradation of HI F1A by CMA. Moreover, we show that HI F1A binds to and is translocated into intact lysosomes isolated from rat livers. This new pathway for degradation of HI F1A does not depend on the presence of oxygen and is activated in response to nutrient deprivation such that the levels of HI F1A bound to CMA positive lysosomes significantly increase in starved animal livers and the binding of HI F1A to LAMP2A increases in response to serum deprivation. Moreover, excessive degradation of HI F1A by CMA compromises cells' ability to respond to and survive under hypoxia, suggesting that this pathway might be of pathophysiological importance in conditions that combine hypoxia with starvation.

Original languageEnglish (US)
Pages (from-to)1349-1366
Number of pages18
JournalAutophagy
Volume9
Issue number9
DOIs
StatePublished - Sep 2013

Keywords

  • Autophagy
  • CHIP
  • CMA
  • HIF1A
  • Hypoxia
  • Metabolism
  • STUB1
  • Starvation
  • Tumor growth
  • Ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Ferreira, J. V., Fofo, H., Bejarano, E., Bento, C. F., Ramalho, J. S., Girao, H., & Pereira, P. (2013). STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy. Autophagy, 9(9), 1349-1366. https://doi.org/10.4161/auto.25190