Abstract
Autophagy is described to be involved in homeostasis, development and disease, both as a survival and a death process. Its involvement in cell death proceeds from interrelationships with the apoptotic pathway. We focused on survival autophagy and investigated its interplays with the apoptotic machinery. We found that while Mcl-1 remained ineffective, Bcl-2 and Bcl-xL were required for starved cells to display a fully functional autophagic pathway as shown by proteolysis activity and detection of autophagic vesicles. Such pro-autophagic functions of Bcl-2 and Bcl-xL were independent of Bax. However they appeared to operate through non redundant mechanisms as Bcl-xL wielded a tighter control than Bcl-2 over the regulation of autophagy: unlike Bcl-2, Bcl-xL and Atg7 manipulation yielded identical phenotypes suggesting they could be components of the same signalling pathway; Bcl-xL subcellular localisation was modified upon starvation, and importantly Bcl-xL acted independently of Beclin 1. Still an intact BH3-binding site was required for Bcl-xL to stimulate a fully functional autophagic pathway. This study highlights that, in addition to their well-established anti-death function during apoptosis, Bcl-2 and Bcl-xL have a broader role in cell survival. Should Bcl-2 and Bcl-xL stand at the cross-roads between pro-survival and pro-death autophagy, this study introduces the new concept that the regulation of autophagy by Bcl-2 and Bcl-xL is adjusted according to its survival or death outcome.
Highlights
Macro-autophagy is a catabolic process orchestrated by the evolutionary conserved ATG genes [1,2], and consist in the random sequestration of macromolecules by newly formed double or multiple membrane bound vesicles called autophagosomes
Stimulation of autophagy was long known as a response to starvation or hormonal stimulation [6]; recent studies have extended the cytoprotective role of autophagy to maintenance of cell viability by showing that ATG genes are necessary for survival in different settings in mammals [7,8,9,10]
The view of Bcl-2 as an anti-autophagic protein [28,29,30] was challenged by the finding that over-expression of Bcl-2 in apoptosis-deficient cells could instead potentiate autophagy [18]. To further investigate this topic, we decided to explore the autophagic functions of Bcl-2 family members under conditions where autophagy stimulation serves as a survival process: similar to what was observed with death-promoting autophagy, we found that survival autophagy is entangled with antiapoptotic functions of Bcl-2 and Bcl-xL; interestingly, they were both found to stimulate autophagy and exhibited different dependence on Beclin 1 to play such pro-survival functions
Summary
Macro-autophagy (hereafter referred to as autophagy) is a catabolic process orchestrated by the evolutionary conserved ATG genes (for autophagy) [1,2], and consist in the random sequestration of macromolecules by newly formed double or multiple membrane bound vesicles called autophagosomes. Stimulation of autophagy was long known as a response to starvation or hormonal stimulation [6]; recent studies have extended the cytoprotective role of autophagy to maintenance of cell viability by showing that ATG genes are necessary for survival in different settings in mammals [7,8,9,10]. In these works, autophagy was elegantly shown to be critical for bioenergetics maintenance and cell viability in vitro, and to play an essential part in vivo in the survival of the whole organism. To further investigate this topic, we decided to explore the autophagic functions of Bcl-2 family members under conditions where autophagy stimulation serves as a survival process: similar to what was observed with death-promoting autophagy, we found that survival autophagy is entangled with antiapoptotic functions of Bcl-2 and Bcl-xL; interestingly, they were both found to stimulate autophagy and exhibited different dependence on Beclin 1 to play such pro-survival functions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
