K63 linked ubiquitin chain formation is a signal for HIF1A degradation by Chaperone-Mediated Autophagy

Ferreira, Joao Vasco; Soares, Ana Rosa; Ramalho, Jose; Pereira, Paulo; Girao, Henrique

http://hdl.handle.net/10362/22425

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Resumo(s)

Chaperone-Mediated Autophagy is a selective form of autophagy. Recently, the degradation of a newly identified CMA substrate, the HIF1A transcription factor, was found to be regulated by the ubiquitin ligase STUB1. In this study we show, for the first time, that K63 ubiquitination is necessary for CMA degradation of HIF1A in vitro and in vivo. Additionally, STUB1 mediates K63 linked ubiquitination of HIF1A. Our findings add a new regulatory step and increase the specificity of the molecular mechanism involved in CMA degradation of HIF1A, expanding the role of ubiquitination to yet another biological process, since the same mechanism might be applicable to other CMA substrates.

Descrição

We thank Dr. Ana Maria Cuervo for providing the shRNA against Lamp2a and Dr. Cam Patterson for the wild-type and mutant STUB1 constructs. This work was supported by grants from the Portuguese Foundation for Science and Technology (FCT), PTDC/SAU-ORG/113542/2009, PTDC/SAU-ORG/118694/2010, PEST-C/SAU/UI3282/2011-COMPETE and UID/NEU/04539/2013 from FCT.

Palavras-chave

INDUCIBLE FACTOR-1-ALPHA HIF-1-ALPHA PROTEASOMAL DEGRADATION TUMOR ANGIOGENESIS FACTOR 1-ALPHA NITRIC-OXIDE LIGASE CHIP RAT-LIVER HYPOXIA PROTEIN PATHWAY General