Contribution of Yeast Studies to the Understanding of BCL-2 Family Intracellular Trafficking.

Akandé Rouchidane Eyitayo,Mathilde Gonin,Stéphen Manon,Hubert Arokium

doi:10.3390/ijms22084086

Abstract

BCL-2 family members are major regulators of apoptotic cell death in mammals. They form an intricate regulatory network that ultimately regulates the release of apoptogenic factors from mitochondria to the cytosol. The ectopic expression of mammalian BCL-2 family members in the yeast Saccharomyces cerevisiae, which lacks BCL-2 homologs, has been long established as a useful addition to the available models to study their function and regulation. In yeast, individual proteins can be studied independently from the whole interaction network, thus providing insight into the molecular mechanisms underlying their function in a living context. Furthermore, one can take advantage of the powerful tools available in yeast to probe intracellular trafficking processes such as mitochondrial sorting and interactions/exchanges between mitochondria and other compartments, such as the endoplasmic reticulum that are largely conserved between yeast and mammals. Yeast molecular genetics thus allows the investigation of the role of these processes on the dynamic equilibrium of BCL-2 family members between mitochondria and extramitochondrial compartments. Here we propose a model of dynamic regulation of BCL-2 family member localization, based on available evidence from ectopic expression in yeast.

Highlights

The ectopic expression of BCL-xL protected yeast against cell death but did not decrease the oxidative stress [48], suggesting a different action of these anti-apoptotic proteins in yeast. All these observations lead to the development of research studies aiming at using yeast as a model to gain knowledge of mammalian BCL-2, including the identification of new partners of BCL-2 family members [49,50,51] and more direct studies aiming to understand how BCL-2 family members cooperate to modulate outer mitochondrial membrane (OMM) permeability and other processes involved in cell death [37,38,39,52,53]
We will focus on yeast studies that have aimed at studying processes and proteins that are involved in the subcellular localization of BCL-2 family members, namely pro-apoptotic BAX and anti-apoptotic BCL-xL, and that contribute to the regulation of the dynamics of this localization, which is closely dependent on the dynamics of intracellular membranes
Like we have reported above, the phosphomimetic mutant BAX-S184D is more susceptible to interact with BCL-xL away from the OMM while the non-phosphorylatable mutant BAX-S184V is more susceptible to interact with BCL-xL in the OMM [68]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The ectopic expression of BCL-xL protected yeast against cell death but did not decrease the oxidative stress [48], suggesting a different action of these anti-apoptotic proteins in yeast All these observations lead to the development of research studies aiming at using yeast as a model to gain knowledge of mammalian BCL-2, including the identification of new partners of BCL-2 family members [49,50,51] (for reviews) and more direct studies aiming to understand how BCL-2 family members cooperate to modulate OMM permeability and other processes involved in cell death [37,38,39,52,53] (for reviews). We will focus on yeast studies that have aimed at studying processes and proteins that are involved in the subcellular localization of BCL-2 family members, namely pro-apoptotic BAX and anti-apoptotic BCL-xL, and that contribute to the regulation of the dynamics of this localization, which is closely dependent on the dynamics of intracellular membranes

Intrinsic Molecular Determinants of BCL-2 Family Members Localization

Stimulation of of mitochondrial localization and activation ferent

Translocation and Retrotranslocation of BAX

Regulators

Concluding Remarks