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STAP-1 to transduce the right signal: adaptors and enzyme association to enhance kinases toward cytokine network

A new study has shed light on the importance of the STAP-1 protein in the activation of some immune cells. The study, published in The Journal of Immunology, investigated how STAP-1 influences the immune response. Researchers have shown that it acts as an intermediary, facilitating communication between different proteins within cells and allowing the transmission of signals from one molecule to another. Understanding the role of STAP-1 in these cells could give researchers better insight into immune-related mechanisms. disorders, such as multiple sclerosis and asthma, and ways to treat them. The researchers found that STAP-1 plays an important role in activating T cells, which play a critical role in defending the body against infections and maintaining overall health. T cells are adept at recognizing foreign antigens that trigger an immune response and mounting targeted responses to eliminate pathogens, such as bacteria and viruses.

T cells need two signals to activate and initiate an immune response. The first signal involves the recognition of antigens presented by other cells, known as antigen-presenting cells. Antigens are recognized by the T cell receptor (TCR), a protein complex on the surface of T cells. The second signal consists of co-stimulatory signals provided by molecules on the antigen-presenting cells. The researchers found that STAP-1 helps T cells communicate and respond to signals, particularly those activated by the T cell receptor. T cells lacking STAP-1 had difficulty receiving and transmitting signals correctly, reducing the production of certain immune molecules called cytokines. The team also found that STAP-1 interacts with other intracellular T cell signaling proteins, forming a complex network that helps regulate their activity. In particular, after activation of the TCR, STAP-1 binds to the tyrosine kinase Itk, activating it.

This enzyme phosphorylates other downstream adapter proteins, protein kinases, and protein phosphatases. Among the latter is calcineurin A, a phosphatase that activates the transcription factor NF-ATc. This is one of the main regulators of the synthesis of interleukin 2 (IL-2), the major activating cytokine of T lymphocytes. The STAP1-Itk complex is then associated with the tyrosine kinase Lck and the enzyme phospholipase C-gamma (PLCγ) which is activated. The enzyme, anchored to the cell membrane, begins to split membrane phospholipids generating second messengers. One of these, DAG, activates protein kinase C (PKC-alpha), the other called IP3 opens the channels of internal calcium stores to release this ion into the cytoplasm and regulate many enzymes and proteins, including calcineurin A. PKC, in turn, triggers the activation of the mitogen-activated protein kinase (MAPK/ERK) signaling pathway, needed for cellular proliferation and committment to immune response.

The researchers then found that cells lacking STAP-1 had less inflammation in models of diseases such as multiple sclerosis and asthma, suggesting that STAP-1 may be involved in the development of these conditions. These findings represent a significant step towards understanding the regulation of the immune system. Future research can build on this work by exploring the potential of STAP-1 as a therapeutic target for the treatment of immune-related disorders. In 2020, the team published another research where they demonstrated that deletion of the STAP-1 protein in natural killer (NK) T lymphocytes worsened the condition of acute autoimmune hepatitis in lab experimental settings. This contrast with the data presented would indicate that STAP-1 has precise functions even within different lymphocyte populations; and that building its pharmacological inhibitors could be advantageous for treating some autoimmune conditions but not others.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Kagohashi K et al. J Immunol. 2024 Mar 15; 212(6):951-961.

Saitoh K, Kashiwakura JI et al. J Immunol. 2022; 209(1):57-68.

Ishiura M et al. Biochem Biophys Res Commun. 2021; 556:185.

Kashiwakura JI et al. PLoS One. 2020 Nov; 15(11):e0241440.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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