DRAM-4 and DRAM-5 are compensatory regulators of autophagy and cell survival in nutrient-deprived conditions

Barthet, V. J.A. , Mrschtik, M., Kania, E., McEwan, D. G., Croft, D., O’Prey, J., Long, J. S. and Ryan, K. M. (2022) DRAM-4 and DRAM-5 are compensatory regulators of autophagy and cell survival in nutrient-deprived conditions. FEBS Journal, 289(13), pp. 3752-3769. (doi: 10.1111/febs.16365) (PMID:35060334)

Abstract

Macroautophagy is a membrane-trafficking process that delivers cytoplasmic material to lysosomes for degradation. The process preserves cellular integrity by removing damaged cellular constituents and can promote cell survival by providing substrates for energy production during hiatuses of nutrient availability. The process is also highly responsive to other forms of cellular stress. For example, DNA damage can induce autophagy and this involves up-regulation of the Damage-Regulated Autophagy Modulator-1 (DRAM-1) by the tumor suppressor p53. DRAM-1 belongs to an evolutionarily conserved protein family, which has five members in humans and we describe here the initial characterization of two members of this family, which we term DRAM-4 and DRAM-5 for DRAM-Related/Associated Member 4/5. We show that the genes encoding these proteins are not regulated by p53, but instead are induced by nutrient deprivation. Similar to other DRAM family proteins, however, DRAM-4 principally localizes to endosomes and DRAM-5 to the plasma membrane and both modulate autophagy flux when over-expressed. Deletion of DRAM-4 using CRISPR/Cas-9 also increased autophagy flux, but we found that DRAM-4 and DRAM-5 undergo compensatory regulation, such that deletion of DRAM-4 does not affect autophagy flux in the absence of DRAM-5. Similarly, deletion of DRAM-4 also promotes cell survival following growth of cells in the absence of amino acids, serum, or glucose, but this effect is also impacted by the absence of DRAM-5. In summary, DRAM-4 and DRAM-5 are nutrient-responsive members of the DRAM family that exhibit interconnected roles in the regulation of autophagy and cell survival under nutrient-deprived conditions.

• Item Type: Articles
• Additional Information: This work was supported by grants from Cancer Research UK (A22903 and A31287).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Long, Dr Jaclyn and Barthet, Valentin and Ryan, Professor Kevin and Croft, Dr Daniel
• Authors: Barthet, V. J.A., Mrschtik, M., Kania, E., McEwan, D. G., Croft, D., O’Prey, J., Long, J. S., and Ryan, K. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: FEBS Journal
• Publisher: Wiley
• ISSN: 1742-464X
• ISSN (Online): 1742-4658
• Published Online: 04 February 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in FEBS Journal 289(13): 3752-3769
• Publisher Policy: Reproduced under a Creative Commons licence