Structural and functional analysis of K11-linked ubiquitin chains and the deubiquitinase Cezanne in the HIF signaling pathway and the cellular adaptation to hypoxia.
Final Report Abstract
The transcription factor HIF-1α is essential for cells to rapidly adapt to low oxygen levels (hypoxia). HIF-1α protein is mainly regulated by the ubiquitin-proteasome system, but complementary control mechanisms have been recently identified, e.g. degradation via chaperone-mediated autophagy. Deregulation of HIF-1α frequently occurs in cancer and correlates with poor patient prognosis. Deubiquitinases (DUBs) are important regulators of ubiquitination events as they oppose the function of E3 ligases. My data show that the K11 linkage-specific DUB Cezanne is crucial for the cellular adaptation to hypoxia as it positively regulates HIF-1α homeostasis. Loss of Cezanne decreased HIF-1α target gene expression due to reduced HIF-1α protein. Mouse embryonic fibroblasts (MEFs) derived from Cezanne knockout mice accumulated less HIF-1α in hypoxia. Surprisingly, the Cezanneregulated degradation of HIF-1α was independent of pVHL as well as PHD hydroxylase or proteasome activity. These observations suggest that Cezanne is essential for HIF-1α protein stability, and that loss of Cezanne stimulates HIF-1α degradation via pVHL- and proteasome-independent routes. Future analyses are necessary to fully elucidate the mechanistic details of how Cezanne controls HIF-1α protein levels, and to assess whether Cezanne can be targeted in von Hippel-Lindau syndrome patients to induce degradation of HIF-1α protein.
Publications
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Emerging roles for Lys11-linked polyubiquitin in cellular regulation. Trends Biochem Sci. 36, 355–363 (2011)
Bremm A, Komander D
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Synthesis and analysis of K11-linked ubiquitin chains. Methods Mol Biol. (2012)
Bremm A, Komander D
