Maja Radulovic uncovers new mechanism of lysosomal membrane repair
first author
Cancer cells are highly dependent on their lysosomes, and damage of lysosome membranes has emerged as a novel strategy for cancer therapy. Maja Radulovic, project leader in Harald Stenmark´s group at Institute for Cancer Research, has previously identified mechanisms that mediate repair of damaged lysosome membranes, including a mechanism involving transfer of lipids from the endoplasmic reticulum (ER) to the damaged lysosome. However, it has remained unclear how efficient lipid transfer is orchestrated. In a recent paper in Nature Cell Biology, Radulovic and her co-workers have identified a new regulator of lysosome repair, the ER protein DFCP1. DFCP1 serves to concentrate lipid channels in ER microdomains that contact the damaged parts of the lysosome, thereby ensuring efficient membrane repair. Because DFCP1 microdomains are regulated by two druggable enzymes, this opens new possibilities for targeting lysosome integrity in cancer therapy.
Lysosomes are the cell´s main compartments for degradation of macromolecules in order to recycle their small-molecule constituents and remove potentially harmful objects such as protein aggregates, damaged organelles, and intracellular pathogens. Because lysosomes contain high concentrations of digestive enzymes, cell death can occur if their content leaks into the cytosol through lesions in the lysosome membrane. While this represents a pathogenic mechanism in neurodegenerative diseases, lysosomal membrane destabilization has emerged as a novel concept for selective killing of cancer cells. This is because cancer cell lysosomes are particularly fragile, and cancer cells normally possess high numbers of lysosomes. Although drugs that destabilize cancer cell lysosomes have been presented, an obstacle to lysosome-directed cancer therapy is the fact that damaged lysosome membranes can be repaired. Maja Radulovic and her co-workers have pioneered studies of lysosomal membrane repair and identified two separate repair mechanisms. One of these entails formation of contacts between damaged lysosomes and the ER, resulting in lipid transfer from the ER to the damaged lysosome membrane, which contributes to membrane repair.
An open question has been how the lipid transfer machinery is focused against the damaged areas of the lysosomes. Now, Radulovic and co-workers have established how this is achieved. They find that calcium ions that leak out of damaged lysosomes activate a protein kinase, ULK1, which in turn activates a lipid kinase, PIK3C3, to produce a specific lipid, phosphatidylinositol 3-phosphate (PI3P) on ER membranes close to the damaged lysosome. This causes formation of microdomains that contain the PI3P-binding ATPase DFCP1. These microdomains serve to gather a lipid channel, VPS13C, in hot spots towards the damaged lysosome membrane, thereby promoting efficient lipid transfer and membrane repair (see Figure). Why is this important? The upstream regulators of DFCP1, ULK1 and PIK3C3, are both druggable enzymes, and this raises the possibility of pharmacologically targeting lysosome repair in cancer cells for lysosome-directed cancer therapy.
This study was a nice team effort within Stenmark´s research group, including former members, but was also strongly facilitated by collaborations with leading international research groups, namely the groups of Max Gutierrez at the Francis Crick Institute (London), Jim Hurley at UC Berkeley, Luis Bonet-Ponce at Ohio State University, and Claudio Bussi at the Nanyang Technological Institute (Singapore).
From left: Sascha Pust, Sebastian Schultz, Maja Radulovic, Harald Stenmark, Andreas Brech, Athanasios Kournoutis, Camilla Raiborg, and Katy McCarron.
Links:
The Nature Cell Biology article (published 15 September 2026):
DFCP1-containing ER microdomains mediate lysosomal membrane repair
Maja Radulovic, Sascha Pust, Athanasios Kournoutis, Di Chen, M. Isabel Giner, Qijian Liang, Santosh Phuyal, Thomas J. Böddeker, Katy McCarron, Eric Herrmann, Kevin Rose, Sebastian W. Schultz, Andreas Brech, James H. Hurley, Claudio Bussi, Luis Bonet-Ponce, Maximiliano G. Gutierrez, Camilla Raiborg & Harald Stenmark
Nature Cell Biology (2026)
Cellular membrane dynamics research group, headed by Harald A. Stenmark