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Unlocking the secrets of ISG15: How does this tiny 17 kDa protein affect our immune system?
In the study of the immune system, a 17 kDa protein has attracted much attention, that is, interferon-stimulated gene 15 (ISG15). This small protein is encoded by the human ISG15 gene and has multiple important functions in the body. As a cytokine, ISG15 not only promotes immune responses, but also plays a regulatory role within cells. This article will explore the structure, function and clinical significance of ISG15, and consider how this small protein may revolutionize our understanding of the immune system.
ISG15: Structure and Properties
The ISG15 gene consists of two exons and encodes a 17 kDa polypeptide. This immature polypeptide is cleaved at its carboxyl terminus to generate a mature 15 kDa product that ends in the toilet tail of LRLRGG, a feature similar to ubiquitin. Although the sequence similarity between ISG15 and ubiquitin is only about 30%, its three-dimensional structure is surprisingly similar, containing two ubiquitin-like domains connected by a peptide chain "hinge". The sequence variation of ISG15 among different species is quite significant, and sometimes the homology between analogues is even as low as 30%.
Function of ISG15
ISG15 will exist in three forms after being stimulated by type I interferon, each form has its own unique function:
1. Extracellular cytokines
ISG15 can be secreted from cells and can be detected in supernatant or plasma. It binds to the LFA-1 integrin receptor on natural killer cells and T cells to promote their production of interferon gamma (IFN-II), which is critical for anti-tuberculosis immunity.
2. Intracellular conjugation: ISGylation
ISG15 is covalently linked to lysine residues on newly synthesized proteins through its C-terminal LRLRGG motif in a manner similar to ubiquitin. This process is called ISGylation and is catalyzed by a series of conjugated enzymes. The major E2 enzyme UBE2E2 is responsible for transferring ISG15 to specific E3 ligases and associated intracellular substrates, and only one specific deconjugating enzyme is currently recognized: USP18.
3. Free internal molecules
Unconjugated ISG15 can negatively regulate IFN-I signaling by preventing SKP2-mediated proteasomal degradation of USP18. Lack of ISG15 results in sustained IFN-I signaling in the human system.
Clinical significance
ISG15 deficiency is a very rare genetic disorder caused by mutations in the ISG15 gene. The disease is inherited in an autosomal recessive pattern, and patients usually develop infectious, neurological, or cutaneous symptoms in childhood. All reported patients developed basal ganglia calcification, which represents an autoinflammatory disease caused by excessive IFN-I activity.
This inflammation may manifest itself early in life in the form of skin ulcers. Some of the patients who have overcome the disease also show incomplete penetration of tuberculosis-like bacteria. Studies have found that in pancreatic ductal adenocarcinoma, tumor-associated macrophages secrete ISG15, further enhancing the characteristics of cancer stem cells.
History of ISG15
ISG15 was first identified in the late 1970s, when it was positioned as a 15-kDa protein produced in response to type I interferons. With the deepening of research, scientists have discovered the antiviral properties of ISG15 and its importance in the immune system, which will have a profound impact on our understanding of the mechanisms of autoimmunity and infection responses.
So, how will this in-depth study of ISG15 impact future immunotherapy or disease treatments?
