DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose

Mrschtik, M., O'Prey, J., Lao, L.Y., Long, J.S., Beaumatin, F., Strachan, D., O'Prey, M., Skommer, J. and Ryan, K.M. (2015) DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose. Cell Death and Differentiation, 22(10), pp. 1714-1726. (doi: 10.1038/cdd.2015.26) (PMID:25929859) (PMCID:PMC4563785)

110963.pdf - Published Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.



Macroautophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. The process operates under basal conditions as a mechanism to turnover damaged or misfolded proteins and organelles. As a result, it has a major role in preserving cellular integrity and viability. In addition to this basal function, macroautophagy can also be modulated in response to various forms of cellular stress, and the rate and cargoes of macroautophagy can be tailored to facilitate appropriate cellular responses in particular situations. The macroautophagy machinery is regulated by a group of evolutionarily conserved autophagy-related (ATG) proteins and by several other autophagy regulators, which either have tissue-restricted expression or operate in specific contexts. We report here the characterization of a novel autophagy regulator that we have termed DRAM-3 due to its significant homology to damage-regulated autophagy modulator (DRAM-1). DRAM-3 is expressed in a broad spectrum of normal tissues and tumor cells, but different from DRAM-1, DRAM-3 is not induced by p53 or DNA-damaging agents. Immunofluorescence studies revealed that DRAM-3 localizes to lysosomes/autolysosomes, endosomes and the plasma membrane, but not the endoplasmic reticulum, phagophores, autophagosomes or Golgi, indicating significant overlap with DRAM-1 localization and with organelles associated with macroautophagy. In this regard, we further proceed to show that DRAM-3 expression causes accumulation of autophagosomes under basal conditions and enhances autophagic flux. Reciprocally, CRISPR/Cas9-mediated disruption of DRAM-3 impairs autophagic flux confirming that DRAM-3 is a modulator of macroautophagy. As macroautophagy can be cytoprotective under starvation conditions, we also tested whether DRAM-3 could promote survival on nutrient deprivation. This revealed that DRAM-3 can repress cell death and promote long-term clonogenic survival of cells grown in the absence of glucose. Interestingly, however, this effect is macroautophagy-independent. In summary, these findings constitute the primary characterization of DRAM-3 as a modulator of both macroautophagy and cell survival under starvation conditions.

Item Type:Articles
Glasgow Author(s) Enlighten ID:O'Prey, Mr James and Long, Dr Jaclyn and Strachan, Mr David and O'Prey, Mrs Margaret and Beaumatin, Dr Florian and Ryan, Professor Kevin
Authors: Mrschtik, M., O'Prey, J., Lao, L.Y., Long, J.S., Beaumatin, F., Strachan, D., O'Prey, M., Skommer, J., and Ryan, K.M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Death and Differentiation
Publisher:Nature Publishing Group
ISSN (Online):1476-5403
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Cell Death and Differentiation 22(10):1714-1726
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record