An international research team has discovered a previously unknown mechanism that plays a key role in the signaling pathways involved in programmed cell death. The team identified the protein HERC4 as an essential component of both TNF-induced necroptosis and apoptosis pathways—two processes that play a crucial role in maintaining cellular balance and triggering inflammatory responses.
The study, “HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death,” was published in Nature Structural and Molecular Biology. The lead researchers were Dr. Sudan He, a professor at the Institute of Systems Medicine at the Chinese Academy of Medical Sciences (CAMS) in Suzhou, China; Dr. Henning Walczak, a professor at the Center for Biochemistry at the University of Cologne and the UCL Cancer Institute at University College London, United Kingdom; and Dr. She Chen, a professor at the National Institute of Biological Sciences (NIBS) in Beijing, China.
Tumor necrosis factor (TNF) is a key messenger substance in the immune system that helps regulate inflammatory processes and defend against pathogens. However, its dysregulation is also associated with severe chronic inflammatory conditions such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis.
TNF triggers two different types of signals through the TNFR1 receptor. Both are capable of triggering an inflammatory response. An initial protein complex, known as Complex I, stimulates the production of signaling molecules that activate the immune system. However, if this physiological inflammatory signal is disrupted by viruses or bacteria, TNF triggers cell death through another protein complex, known as Complex II.
In previous studies, Walczak’s team demonstrated that cell death triggered through ComplexII signals the immune system to mobilize. If an infection is present, this switch is essential for eliminating infected cells and enabling the immune system to fight the infection. However, if the process malfunctions, cell death triggered by TNF can severely damage or even destroy entire organs or organ systems through acute or persistent inflammation. This is the case with conditions such as rheumatism, IBD or psoriasis.
For this reason, TNF inhibitors are among the most medically valuable and commercially successful medicines of the last three decades worldwide. However, TNF inhibitors are not tablets; they must be administered by injection.
HERC4 as the missing link: From survival signaling to death signaling
Until now, it has been unclear how the TNF signaling pathway switches from a survival signal to a death signal for cells. In their latest study, the research group led by He, Walczak and Chen demonstrated that the E3 ubiquitin ligase protein HERC4 acts as this critical switch.
Based on previous data, the team used a knockout screen to identify proteins involved in the ubiquitination of RIPK1. Ubiquitination is a process in which proteins are marked with the small protein ubiquitin to prepare them for further processes within the cell. RIPK1 is the key protein in Complex I and Complex II. HERC4 was the only previously unknown candidate whose knockout resulted in cell survival when the cells were treated with a cocktail of active ingredients that induced TNF-mediated cell death.
The group found that HERC4 binds to kinase-active RIPK1 from the survival signaling pathway (Complex I), ubiquitinates it and thus initiates the formation of Complex II—comprising RIPK1, RIPK3, FADD, caspase-8 and cFLIP—which triggers cell death. Depending on the relative expression levels of these proteins, the affected cells die by either apoptosis or necroptosis.
This discovery not only explains why RIPK1 kinase activity is required for both necroptosis and apoptosis but also solves a decades-old mystery in TNF research: how RIPK1 ensures a cell’s survival in Complex I yet triggers its death in Complex II.
“HERC4 is therefore not only a previously missing piece of the puzzle in TNF signal transduction,” says Walczak, “but also a promising therapeutic target. After all, many chronic inflammatory diseases arise precisely where this signaling pathway is dysregulated.”
Therapeutic potential: A new target for drugs
Mouse models have shown that mice lacking HERC4 are protected against TNF-induced systemic inflammatory responses and TNF-mediated acute liver damage. These are different pathological inflammatory processes, triggered by uncontrolled necroptosis and apoptosis, respectively. The discovery of HERC4 opens up new possibilities for treating rheumatoid arthritis, inflammatory bowel disease (IBD) and psoriasis, as well as other TNF-associated conditions such as sepsis or certain types of cancer.
“This discovery is a milestone in our understanding of inflammatory processes mediated by cell death,” says Walczak. “It demonstrates how findings from basic science can have direct clinical relevance, which underlines the real importance of basic research for clinical translation.”
Next, the team plans to develop low-molecular-weight HERC4 inhibitors that can be taken orally. The researchers speculate that HERC4 inhibitors could have a broader spectrum of activity than TNF inhibitors, and they are investigating that possibility.
https://medicalxpress.com/news/2026-09-piece-cell-death-inflammation-pathway.html
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