The study highlights the key role of a protein called TECPR1 in cellular response to damage of the internal membranes. They found that TECPR1 triggers the attachment of ATG8 proteins to damaged membranes, in a process referred to as non-canonical autophagy, acting as a signal for the presence of harmful substances or pathogens. This understanding of cellular response to membrane damage has important implications for improving drug delivery, as it can help enhance the effectiveness of medical treatments by improving endosomal escape to facilitate access of drugs to the inside of cells.
Their research unveiled that TECPR1 is activated by the exposure of sphingomyelin (SM) at sites of membrane damage. The team also discovered that TECPR1 recognizes and binds to sphingomyelin (SM) through its DysF domains. This binding enables TECPR1, in conjunction with the ATG5-ATG12 complex, to facilitate the attachment of ATG8 to the damaged membrane, even in the presence of a bacterial pathogenic factor that blocks the complementary complex containing ATG16L1. Intriguingly, while TECPR1-mediated ATG8 lipidation relies on SM, the presence of SM does not impact ATG16L1-containing complexes. Overall, this study significantly enhances our understanding of non-canonical autophagy mechanisms and demonstrates the essential role played by TECPR1 in cellular responses to membrane damage.
The findings were recently published in the EMBO journal, appearing back-to-back with a complementary article from the lab of Felix Randow. Additionally, an EMBO report from the Wu lab and a preprint on bioRxiv by the Wileman lab also explored the recognition of membrane damage by TECPR1 and the resulting ATG8 labeling of the damaged compartments. These studies, all released this summer, demonstrated consistent TECPR1 function utilizing diverse stimuli to induce damage.