Ras pathway signaling accelerates programmed cell death in the pathogenic fungus Candida albicans

Abstract

A better understanding of the molecular basis of programmed cell death (PCD) in fungi could provide information that is useful in the design of antifungal drugs that combat life-threatening fungal infections. Harsh environmental stresses, such as acetic acid or hydrogen peroxide, have been shown to induce PCD in the pathogenic fungus Candida albicans. In this study, we show that dying cells progress from an apoptotic state to a secondary necrotic state and that the rate at which this change occurs is proportional to the intensity of the stimulus. Also, we found that the temporal response is modulated by Ras-cAMP-PKA signals. Mutations that block Ras-cAMP-PKA signaling (ras1⌬, cdc35⌬, tpk1⌬, and tpk2⌬) suppress or delay the apoptotic response, whereas mutations that stimulate signaling (RAS1 val13 and pde2⌬) accelerate the rate of entry of cells into apoptosis. Pharmacological stimulation or inhibition of Ras signaling reinforces these findings. Transient increases in endogenous cAMP occur under conditions that stimulate apoptosis but not growth arrest. Death-specific changes in the abundance of different isoforms of the PKA regulatory subunit, Bcy1p, are also observed. Activation of Ras signals may regulate PCD of C. albicans, either by inhibiting antiapoptotic functions (such as stress responses) or by activating proapoptotic functions.apoptosis ͉ cAMP ͉ necrosis

A MAP Kinase Pathway Is Implicated in the Pseudohyphal Induction by Hydrogen Peroxide in Candica albicans

“…A recent study suggested a Ras-cAMP-PKA signaling in the apoptotic response to weak acid exposure, but demonstrated that cells treated with 25 mM H 2 O 2 for 30 min rarely undergo apoptosis (Phillips et al, 2006). This finding implies that it may be difficult to find candidate effector genes at an early stage of apoptosis among toxic up-regulated genes in our experimental condition.…”

Elevated Ras/protein kinase A activity in Saccharomyces cerevisiae reduces proliferation rate and lifespan by two different reactive oxygen species‐dependent routes

“…As with other organisms, elevated levels of ROS appear to be a key element triggering the yeast ALP, and the pathway shares several apoptotic regulator components with that of higher organisms, including a metacaspase and a caspase-regulating serine protease (Madeo et al, 2004). Interestingly, in the fungus Candida albicans, mutations that block Ras-cAMP-PKA signaling suppress or delay the apoptotic response, whereas mutations that stimulate Ras signaling accelerate the rate of entry of cells into apoptosis (Phillips et al, 2006). In addition, stabilization of the actin cytoskeleton leads to activation of the yeast ALP via hyperactivation of the Ras signaling pathway (Gourlay & Ayscough, 2006).…”

Whi2p links nutritional sensing to actin-dependent Ras-cAMP-PKA regulation and apoptosis in yeast

“…The ability of the RascAMP-PKA pathway to regulate mitochondrial function and ROS production also appears to have been harnessed by a fungal apoptotic response. This has been demonstrated in both the fungal pathogen Candida albicans (Phillips et al, 2006;Phillips et al, 2003) and the budding yeast S. cerevisiae (Gourlay and Ayscough, 2005;. The Ras-cAMP-PKA pathway therefore provides a good potential link from environmental sensing to the processes of apoptosis and ageing in yeast.…”