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When Phosphatases Go Mad: The Molecular Basis for Toxicity of Yeast Ppz1
Antonio Casamayor1, Joaquín Ariño1
1Institut de Biotecnologia i Biomedicina & Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.
Abstract:
The fact that overexpression of the yeast Ser/Thr protein phosphatase Ppz1 induces a dramatic halt in cell proliferation was known long ago, but only work in the last few years has provided insight into the molecular basis for this toxicity. Overexpression of Ppz1 causes abundant changes in gene expression and modifies the phosphorylation state of more than 150 proteins, including key signaling protein kinases such as Hog1 or Snf1. Diverse cellular processes are altered: halt in translation, failure to properly adapt to low glucose supply, acidification of the cytosol, or depletion of intracellular potassium content are a few examples. Therefore, the toxicity derived from an excess of Ppz1 appears to be multifactorial, the characteristic cell growth blockage thus arising from the combination of various altered processes. Notably, overexpression of the Ppz1 regulatory subunit Hal3 fully counteracts the toxic effects of the phosphatase, and this process involves intracellular relocation of the phosphatase to internal membranes.
Insights
Overexpressing yeast Ser/Thr protein phosphatase Ppz1 halts cell growth by altering gene expression and protein phosphorylation. The regulatory subunit Hal3 counteracts this toxicity by relocating Ppz1.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The toxicity of yeast Ser/Thr protein phosphatase Ppz1 (Ppz1) overexpression on cell proliferation has been recognized.
- Recent research has begun to elucidate the molecular mechanisms underlying Ppz1-induced toxicity.
Purpose of the Study:
- To investigate the multifactorial molecular basis of Ppz1 overexpression toxicity in yeast.
- To understand how the regulatory subunit Hal3 counteracts Ppz1 toxicity.
Main Methods:
- Analysis of gene expression changes due to Ppz1 overexpression.
- Phosphoproteomic analysis to identify modified proteins.
- Observation of cellular process alterations and protein localization.
Main Results:
- Ppz1 overexpression significantly alters gene expression and the phosphorylation state of over 150 proteins, including kinases Hog1 and Snf1.
- Key cellular processes affected include translation, glucose metabolism, cytosolic pH, and potassium homeostasis.
- Overexpression of the regulatory subunit Hal3 completely reverses Ppz1 toxicity, involving Ppz1's relocation to internal membranes.
Conclusions:
- Ppz1 overexpression toxicity is multifactorial, resulting from a combination of disrupted cellular processes.
- Hal3 plays a crucial role in mitigating Ppz1 toxicity through a mechanism involving protein relocation.
