Most intracellular signaling cascades rely on the formation of multiprotein signaling complexes assembled in large protein signaling platforms. Especially in cell death signaling, there is a large variety of these complexes, including the apoptosome, the necrosome, or the death-inducing signaling complex (DISC), to name only a few. During the last years, a number of cellular conditions were identified that lead to the formation of another signaling platform, the so-called ripoptosome. Diverse stimuli such as genotoxic stress, death receptor or Toll-like-receptor (TLR) ligation, or degradation of cellular inhibitor of apoptosis proteins (cIAPs) are able to induce ripoptosome formation. The ripoptosome is tightly regulated by cIAPs that control intracellular RIP1 assembly and the association with other cell death-regulating proteins, most likely by ubiquitin linkage. The suppression of cIAP activity results in accumulation of RIP1 platforms that ultimately triggers necroptosis by activation of RIP3-MLKL-dependent necrosis signaling pathways.
The ripoptosome is a 2-MDa protein complex, which consists of the core components caspase-8, FADD, different cFLIP isoforms, and RIP1. It represents one of the rheostats in cell death signaling, as it can activate apoptotic and necroptotic cell death responses. The specific formation and activation of the ripoptosome in cancer but not in primary cells suggests that this complex is a potential novel target for cancer or anti-inflammatory therapy, as suggested by the potential proinflammatory effects of necroptosis. Therefore, beside novel cancer therapeutics, the importance of this molecula platform spans also for the development of new therapies for inflammatory diseases, e.g. asthma or inflammatory bowel dosease. Indeed, a latest discovery about a built-in rapid reaction system that triggers inflammatory responses when people are exposed to allergens, also may hold the keys to helping more people manage their allergies in years to come. A study led by scientists at Cincinnati Children’s and published in Nature Immunology reveals new details about how the body’s “type 2 innate immune response” system works.
By identifying a common biological response platform, the findings suggest that any new medication that can control the response could benefit people suffering from a wide range of allergies. Previous research had established that multiple allergens can induce a similar IL-33 response upon breaching the epithelial layer of mucosal membranes. The Cincinnati Children’s team pinned down the mechanisms at work in the process. This breakthrough was made possible by new insights into role of ripoptosome signaling and caspases in allergic inflammation. Specifically, the allergens trigger activity among an interlocked set of cell death-inducing signals called the ripoptosome. This signaling “platform” includes numerous components, but for allergic inflammatory reactions, the key player appears to be a molecular switch called caspase 8. The investigators named the pathway, “RipIL-33” as IL-33 is processed (ripped) by the ripoptosome. In the last two decades, immunologists have discovered the mechanisms by which bacteria and viruses are sensed by the innate immune system.
However, how allergens are sensed has remained a mystery. Usually Toll receptors And receptor immunoglobulins (IgGs) have been invoked as general external sensors, but the discovery of this surprising mechanism is the most important breakthrough in understanding how the innate immune system senses allergens to initiate a type 2 response and subsequent allergic inflammation. In mice, inhibiting the activity of the keller enzyme caspase 8 reduced the IL-33 response to allergen exposure and limited bronchial inflammation in the lungs. Further analyses indicated that a similar process occurs in humans. In the human allergic disease eosinophilic esophagitis (EoE), this team found that ripoptosome activation markers and mature IL-33 levels dynamically correlated with the degree of esophageal eosinophilia and disease activity. In their next steps, scientists will seek further confirmation of the RipIL-33 pathway in human allergic reaction and determining whether existing or new drugs can safely disrupt the inflammation cycle.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Brusilovsky M, Rochman M et al. Nature Immunol 2021 Sept 16.
Brusilovsky M et al. J Clin Invest. 2020 Jul 1; 130(7):3419-3421.
Wong J et al. Cell Mol Gastroenterol Hepatol. 2020; 9(2):295-12.
Feng Y et al. Proc Natl Acad Sci USA. 2019; 116(30):15170-177.
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Dott. Gianfrancesco Cormaci
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