• - Discovery of a key regulatory checkpoint of autophagy through multidisciplinary research…providing new clues for the treatment of human diseases including cancer
• - Research findings published in Autophagy (IF=14.3), a world-leading journal in the fields of cell biology and molecular biology

Figure Description: (From left) Corresponding authors Prof. Yong Yeon Cho of the College of Pharmacy at The Catholic University of Korea, and Drs. Bang Geul and Cheol Joong Lee of Korea Basic Science Institute (KBSI), along with first authors Subin Nam, Ph.D. candidate at the College of Pharmacy of The Catholic University of Korea, and Dr. Gaeun Lee of KBSI

A research team led by Prof. Yong Yeon Cho from the College of Pharmacy at The Catholic University of Korea has discovered a key regulatory switch for autophagy, often referred to as the cell’s “waste disposal system.” Through collaborative research with Dr. Cheol Joong Lee’s team at Korea Basic Science Institute (KBSI), the researchers identified a novel molecular mechanism regulating autophagy, a critical pathway involved in cellular survival, aging, and death.

Autophagy is a cellular recycling system in which damaged proteins or organelles are degraded through membrane fusion with lysosomes and subsequently utilized as an energy source necessary for cell survival. The central focus of this study, DRAM2 (DNA damage-regulated autophagy modulator 2), is a protein containing six transmembrane domains that activates the early stages of autophagy under cellular stress conditions.

The research team successfully elucidated the previously unknown functional role of DRAM2. Their findings revealed that although DRAM2 itself lacks enzymatic activity, it regulates autophagic flux through interaction with AP3D1/AP-3. In particular, phosphorylation by the kinase RSK2 was identified as the key molecular switch governing this process.

In addition, the team confirmed that RSK2 phosphorylates a specific amino acid residue of DRAM2 and that this signaling axis plays a decisive role in vesicular transport from endosomes to lysosomes. These findings establish a novel signaling pathway governing the dynamic interactions between biological membranes and membrane trafficking, while also demonstrating the possibility of precisely controlling autophagic pathways.

Notably, this study maximized the completeness and reliability of its findings through multidisciplinary research approaches. The team employed a wide range of techniques, including △overexpression of mutant proteins △analysis of endogenous proteins △mass spectrometry and high-resolution fluorescence microscopy △bioinformatics and computational structural analysis, to validate the molecular mechanism. Furthermore, validation experiments using animal models confirmed the physiological relevance of the findings in vivo.

The study was published online on May 3 in Autophagy (IF=14.3), one of the world’s leading journals in cell biology and molecular biology. Prof. Yong Yeon Cho of the College of Pharmacy at The Catholic University of Korea and Drs. Bang Geul and Cheol Joong Lee of KBSI served as corresponding authors, while Subin Nam, a Ph.D. candidate at the College of Pharmacy of The Catholic University of Korea, and Dr. Gaeun Lee of KBSI participated as first authors.

Prof. Yong Yeon Cho of The Catholic University of Korea stated, “This study is significant in that it elucidates a novel mechanism underlying intracellular vesicle dynamics. As the RSK2-DRAM2 signaling axis has been identified as a new regulatory checkpoint controlling autophagic flux, we hope that it can serve as a foundational technology for the development of therapeutic strategies and treatments for various human diseases, including cancer.”

(Figure 1) Protein interaction binding structure between DRAM2 and RSK2

Using a computational docking model, the cytoplasmic region of DRAM2 was predicted to form stable interactions with RPS6KA3/RSK2 through hydrogen bonding, carbon-hydrogen bonding, salt bridges, sulfur-X interactions, and hydrophobic contacts (predicted binding energy: −73.924 kcal/mol).

(Figure 2) Identification of DRAM2–AP3D1/AP-3 interaction and RSK2-mediated phosphorylation required for lysosomal trafficking

For DRAM2 to be transported to lysosomes, it must first be recognized and bound by AP3D1/AP-3.
The cytoplasmic region of DRAM2 contains a conserved RxRxxS amino acid motif targeted for phosphorylation by RSK2.
Replacement of the serine residue within this conserved motif with alanine prevented trafficking to lysosomes.
(Green: GFP-DRAM2 protein; Red: AP3D1 protein; Blue: genome)