Image Credit: Courtesy of University of Cologne
Scientific Frontline: Extended "At a Glance" Summary: HERC4 and TNF-Induced Cell Death
The Core Concept: HERC4 is a newly identified protein that acts as a crucial switch in cellular signaling, determining whether a cell survives or undergoes programmed cell death.
Key Distinction/Mechanism: Tumor necrosis factor (TNF) normally signals for cell survival and inflammation via Complex I; HERC4 alters this by binding to and ubiquitinating the RIPK1 protein, which shifts the signaling to Complex II, triggering either apoptosis or necroptosis (cell death).
Origin/History: The discovery of HERC4's role was published in Nature Structural and Molecular Biology (announced September 2026) by a joint international research team from China and the UK/Germany, solving a long-standing mystery regarding TNF signaling.
Major Frameworks/Components:
- Tumor necrosis factor (TNF): An immune system messenger regulating inflammation.
- HERC4: An E3 ubiquitin ligase protein responsible for the critical switching mechanism.
- RIPK1: A key kinase protein involved in both survival (Complex I) and death (Complex II) pathways.
- Ubiquitination: A cellular process where proteins are tagged with ubiquitin, altering their function or destiny.
- Complex I and Complex II: Protein groupings that dictate cell survival/inflammation (I) or programmed cell death (II).
Branch of Science: Biochemistry, Molecular Biology, Immunology.
Future Application: The development of orally administered low-molecular-weight HERC4 inhibitors to treat chronic inflammatory diseases and potentially inflammation-related cancers.
Why It Matters: Dysregulation of TNF-induced cell death causes severe inflammatory damage to organs. Targeting HERC4 offers a new, potentially broad-spectrum therapeutic approach for conditions like rheumatoid arthritis, inflammatory bowel disease, psoriasis, and sepsis, improving upon current injectable TNF inhibitors.
An international research team has discovered that the protein HERC4 is a key component in the signaling pathways involved in programmed cell death, which is responsible for triggering inflammatory diseases. The discovery will potentially lead the way to new therapeutic approaches for chronic inflammatory bowel diseases, rheumatism, and psoriasis, as well as for inflammation-related types of cancer.
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 has 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, entitled “HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death,” was published in the journal Nature Structural and Molecular Biology. The lead researchers were Dr. Sudan He of the Institute of Systems Medicine at the Chinese Academy of Medical Sciences (CAMS) in Suzhou, China; Dr. Henning Walczak of the Center for Biochemistry at the University of Cologne and the UCL Cancer Institute at University College London, United Kingdom; and Dr. She Chen of the National Institute of Biological Sciences (NIBS), Beijing, China.
Tumor necrosis factor (TNF) is a key messenger substance in the immune system that plays a role in regulating inflammatory processes and defending 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 via the TNFR1 receptor. Both are capable of triggering an inflammatory response: via an initial complex, known as Complex I, the production of various signaling molecules is stimulated. These then stimulate the immune system. However, if this physiological inflammatory signal is disrupted by viruses or bacteria, TNF triggers cell death via another protein complex, known as Complex II.
In previous studies, Walczak’s team had already demonstrated that cell death triggered via Complex II acts as a signal to the immune system, prompting a general mobilization. If an infection is present, this switching process is essential for eliminating infected cells and enabling the immune system to fight off the infection. However, if there is a dysfunction, the cell death triggered by TNF can cause severe damage to, or even destroy, entire organs or organ systems as a result of 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 to patients by injection.
HERC4 as the Missing Link: From Survival Signaling to Death Signaling
Until now, it has remained 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 has demonstrated that the E3 ubiquitin ligase protein HERC4 acts as this critical switching point. Based on previous data, the team used a knockout screen to specifically 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. Biochemically, the group discovered 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 various proteins, the affected cells die either by apoptosis or necroptosis.
This discovery therefore 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 it is that RIPK1 ensures the survival of the cell in Complex I, yet triggers cell 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 or apoptosis, respectively. The discovery of HERC4 therefore opens new possibilities for the development of treatments for 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 Henning 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 administered orally. The researchers speculate that HERC4 inhibitors could have a broader spectrum of activity than TNF inhibitors, and this is currently being investigated.
Published in journal: Nature Structural & Molecular Biology
Title: HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death
Authors: Haohao Lu, Tongde Du, Lin Li, Dongmei Cao, Ke Li, Linjie Liu, Rui Li, Xiaoliang Yu, Shouqiao Hou, Xinhui Wang, Minyan Shi, Yanfen Liu, Feng Ma, She Chen, Henning Walczak, and Sudan He
Source/Credit: University of Cologne
Edited by: Scientific Frontline
Reference Number: bchm092826_01