Roles of Lysine-63-linked ubiquitination on Hif-1α in cell fate decisions between cell proliferation and apoptosis under cadmium effects in epithelial cells

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Abstract Lysine-63-linked ubiquitination -, i.e., The conjugation of a chain of ubiquitins linked through lysine63 has emerged as a key mechanism regulating signal transduction pathways. Although critical, very little information is currently available about how subversion of lysine 63 ubiquitination might contribute to cancers and inflammatory diseases. The present study provides evidence that cadmium, a carcinogenic and toxic substance released into the environment, is a powerful activator of lysine-63 ubiquitination. Indeed, cadmium induces the accumulation of lysine-63-polyubiquitination proteins. Importantly, cadmium-induced ubiquitination does not stem oxidative damage or proteasome impairment. Rather, we demonstrate that cadmium not only activates Lysine 63 ubiquitination but also amplifies its accumulation by overloading the capacity of the autophagy pathway, thus promoting endoplasmic reticulum stress and cell death. At the molecular level, cadmium-induced ubiquitination is correlated with the stabilization of hypoxia inducible factor-1-alpha, a transcription factor. Strikingly, prolonged cell exposure to high cadmium concentrations induces exaggerated lysine-63 ubiquitination that fosters aggresome formation, thus precluding this protein from interacting with its downstream nuclear targets. We therefore propose that the aberrant activation of lysine-63 ubiquitination by the carcinogen cadmium could promote cell proliferation and inflammation at low levels, while high levels lead to cell death.

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