Systemic autoinflammatory diseases (SAIDs) are a group of disorders driven by dysregulated innate immune activation. Previous studies highlighted that mutations in genes involved in programmed cell death (PCD) pathways play central roles in this disease pathogenesis. However, the mechanisms linking dysregulated cell death to the inflammatory responses remain incompletely understood.

In a study published online in the Proceedings of the National Academy of Sciences (PNAS) on April 7, 2026, a research team led by Prof. ZHANG Haibing from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences uncovered a novel mechanism by which RIPK1 ubiquitination regulates both cell death and inflammation.

Receptor-interacting protein kinase 1 (RIPK1) is a key molecular hub that integrates cell death and inflammatory signaling. Its activity is tightly controlled by post-translational modifications. Among them, K63-linked ubiquitination at lysine 376 (K376) has been shown to suppress apoptosis and necroptosis. However, its role in regulating inflammation has remained unclear. Human genetic studies further indicated that dysregulation of RIPK1 is closely associated with autoinflammatory diseases: loss-of-function mutations cause immunodeficiency, cleavage-resistant variants lead to dominant autoinflammatory syndromes, and recent identification of ubiquitination-defective variants (K377E/R390G) suggested a direct link between impaired ubiquitination and systemic inflammation.

To address these questions, the researchers generated multiple genetically engineered mouse models. Building on their previous work showing that K376 ubiquitination is essential for normal development, they introduced a kinase-inactive mutation (D138N) into Ripk1^K376R mice. Researchers found that loss of K376 ubiquitination led to aberrant RIPK1 activation, causing excessive cell death and embryonic lethality via a kinase-dependent mechanism. Notably, inactivation of RIPK1 kinase activity rescued embryonic lethality but resulted in progressive systemic inflammation in adult mice, including skin and liver inflammation, splenomegaly, and immune dysregulation.

Mechanistically, the researchers demonstrated that the RIPK1 K376R mutation not only affects its kinase activity but also promotes inflammation through its scaffold function. Specifically, this mutation triggers intrinsic activation of the NLRP3 inflammasome, leading to increased IL-1β secretion.

Genetic analyses revealed that deletion of Caspase-1/11 significantly alleviated inflammation, whereas TRIF deficiency had no effect, highlighting the central role of inflammasome signaling. Furthermore, this inflammatory process was found to be independent of MLKL-mediated necroptosis but dependent on RIPK3 and Caspase-1/11, revealing a noncanonical inflammatory pathway.

This work systematically elucidated how RIPK1 ubiquitination governs the balance between cell death and inflammation, uncovering a dual regulatory mechanism involving kinase-dependent cell death and kinase-independent inflammatory signaling. It provided critical mechanistic insights into how RIPK1 signaling drives autoinflammation and offered potential diagnostic markers and therapeutic targets for SAIDs.

Paper link: https://doi.org/10.1073/pnas.2520356123

Scientific Contact:
Prof. ZHANG Haibing
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: hbzhang@sinh.ac.cn

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn