**Abstract:** A recent study by the laboratory of Professor Min Zhang at Tsinghua University's School of Pharmaceutical Sciences has unveiled a critical molecular target that explains the mechanism behind the excessive inflammation caused by severe coronavirus infections, including SARS-CoV-2, SARS-CoV, and MERS-CoV. The research, published in *Nature Communications* on October 8, 2023, under the title "Coronavirus Envelope Protein Activates TMED10-Mediated Unconventional Secretion of Inflammatory Factors," provides a detailed understanding of how the envelope protein (E) of severe coronaviruses stimulates the release of inflammatory cytokines, leading to a cytokine storm—a significant cause of severe illness and mortality in infected patients. **Key Events and Findings:** 1. **Identifying the Role of E Protein:** - The study focused on the impact of various membrane proteins from severe coronaviruses on the secretion of inflammatory cytokines. - The envelope protein (E) was found to strongly induce the release of cytokines such as IL-1β, which are critical in causing the cytokine storm. - Compared to membrane proteins from mild coronaviruses, the E protein from severe coronaviruses was significantly more potent in stimulating cytokine release. 2. **Mechanism of E Protein Action:** - The researchers discovered that the E protein interacts strongly with the host membrane protein TMED10. - This interaction activates the TMED10-channeled unconventional protein secretion (THU) pathway, which is responsible for the transport of non-classical secretory proteins like cytokines. - The THU pathway involves the formation of a protein transporter by the oligomerization of TMED10, facilitating the movement of cytokines across the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and their subsequent secretion. 3. **ERGIC Function in Non-Classical Secretion:** - The ERGIC, a key intracellular membrane compartment, has specialized functional zones that mediate the transmembrane transport of non-classical secretory proteins. - The study highlights the importance of these functional zones in the THU pathway and the role they play in exacerbating the inflammatory response during severe coronavirus infections. 4. **Potential Therapeutic Target:** - The researchers identified a class of progesterone-like small molecules that can inhibit the interaction between the E protein and TMED10. - These molecules effectively reduce the secretion of inflammatory cytokines and mitigate the inflammatory response in the host. - The E-TMED10 interaction is proposed as a potential therapeutic target for treating the adverse inflammatory reactions induced by severe coronaviruses. **Implications and Future Directions:** The findings of this study not only elucidate the molecular mechanisms underlying the excessive inflammation caused by severe coronaviruses but also suggest new avenues for therapeutic intervention. By targeting the E-TMED10 interaction, it may be possible to develop drugs that prevent or reduce the cytokine storm, thereby lowering the severity and mortality rates associated with these infections. This research could provide valuable insights for the development of treatments and strategies to combat future coronavirus outbreaks. **Acknowledgments:** Professor Min Zhang, an associate professor at Tsinghua University's School of Pharmaceutical Sciences, is the corresponding author of the study. The lead authors are Dr. Lei Liu, a postdoctoral fellow at the School of Pharmaceutical Sciences, and Jingyao Zhang, a 2020 PhD student at the School of Life Sciences. The research was significantly supported by Associate Professor Liang Ge from the School of Life Sciences, Researcher Boxue Tian from the School of Pharmaceutical Sciences, and Professor Peihui Wang from Shandong University. The study was funded by the National Natural Science Foundation of China, the Vanke Foundation, and Tsinghua University's Dushí Project. **Link to the Paper:** - https://www.nature.com/articles/s41467-024-52818-0 **Source:** - Tsinghua University School of Pharmaceutical Sciences - Edited by Huashan Li - Reviewed by Ling Guo