The product of the UTH1 gene, required for Bax‐induced cell death in yeast, is involved in the response to rapamycin

Abstract

SummaryA yeast mutant was isolated that was resistant to Baxinduced cell death. It supports a mutation leading to decreased amounts of the protein Uth1p. A strain in which the UTH1 gene is disrupted also exhibits resistance to Bax expression. The absence of Uth1p does not change the mitochondrial localization of Bax, its insertion in the mitochondrial outer membrane or its cytochrome c -releasing activity. On the other hand, the absence of Uth1p does prevent the appearance of other hallmarks related to Bax expression in yeast, such as oxidation of mitochondrial lipid, production of reactive oxygen species and maintenance of plasma membrane properties after ethanol stress. The absence of Uth1p was also found to induce resistance to rapamycin, a specific inducer of autophagy. This resistance only appears when cells are grown under respiratory conditions, but not under fermentative conditions, suggesting that Uth1p acts in an autophagic pathway involving mitochondria, in accordance with its main localization in the outer mitochondrial membrane. Taken together, these data show that Bax is able to activate a death pathway related to autophagy in yeast, which also exhibits typical hallmarks of apoptosis, revealing a possible dual function of Bax in both types of death. This hypothesis is discussed in the light of observations suggesting a coregulation of apoptosis and autophagy in mammalian cells.

7-Ketocholesterol Induces Protein Ubiquitination, Myelin Figure Formation, and Light Chain 3 Processing in Vascular Smooth Muscle Cells

“…25 However, accumulation of ubiquitin-conjugated proapoptotic proteins did not give rise to a higher incidence of apoptotic cell death. There is a possibility that certain proapoptotic proteins have a function in apoptosis and autophagic cell death, as proposed recently for Bax by Camougrand et al 29 Interestingly, the core protein machinery necessary to drive formation of autophagosomes includes a ubiquitin-like protein conjugation system. 16,22 Moreover, Kostin et al 8 reported that autophagic vacuoles are positive for ubiquitin immunolabeling.…”

Autophagy and cell death in model organisms

“…In addition, Uth1 mutants survive and proliferate when expressing the human proapoptotic cell death gene bax. 47 The totality of these findings suggests that Uth1p may provide a direct association between mitophagy and cell death.…”

The mitochondrial pathway in yeast apoptosis

“…UTH1, a gene that is possibly involved in autophagic death, is needed for efficient Baxmediated killing in yeast [74]. While deletion of UTH1 does not prevent the insertion of Bax into the mitochondrial outer membrane or cytochrome c release, it inhibits the appearance of mitochondrial lipid oxidation and ROS production [74], suggesting an additional cytochrome c independent but autophagy-related pathway of Bax triggering cell death. Furthermore, UTH1 is involved in various types of stress response and ageing [75,76] and its deletion confers resistance to rapamycin [74].…”