Interferon-Stimulated Gene 15 (ISG15) is a small protein involved in the body’s defense mechanisms. It belongs to the ubiquitin-like modifier (UBL) family, sharing structural similarities with ubiquitin. ISG15 is rapidly produced in response to interferons, which are signaling molecules released by cells during infections to activate immune responses. This rapid production highlights ISG15’s involvement in cellular defense.
How ISG15 Modifies Proteins
ISG15 modifies other proteins through a process called ISGylation. This process is a type of post-translational modification, meaning it occurs after a protein has been made. ISGylation involves a cascade of enzymatic reactions, mirroring the steps seen in ubiquitination, but with distinct outcomes.
The ISGylation pathway begins with an E1 activating enzyme, UBA7, which forms a high-energy bond with ISG15, requiring ATP. The activated ISG15 is then transferred to an E2 conjugating enzyme, UBCH8, forming a covalent bond. Finally, an E3 ligase enzyme facilitates the attachment of ISG15 to a lysine residue on the target protein. This attachment can change the target protein’s function, stability, or location within the cell.
ISG15’s Role in Fighting Infections
ISG15 plays an important role in the innate immune response, particularly against viral infections. ISGylation can directly interfere with various stages of the viral life cycle. For instance, it can inhibit the budding and release of viral particles by disrupting host proteins involved in viral assembly.
ISG15 can also target viral proteins, altering their function. For example, ISGylation of the NS1 protein of Influenza A virus inhibits its function and virus replication. The modification of host proteins by ISG15 can promote an antiviral state within cells. ISGylation of the viral sensor IFIH1/MDA5 enhances its ability to detect viruses and activate innate immunity against various pathogens, including coronaviruses and flaviviruses.
Beyond direct antiviral mechanisms, ISG15 also contributes to broader immune responses. It can promote the polarization of macrophages towards an M1 phenotype, which is associated with increased production of antiviral factors like reactive oxygen species (ROS) and nitric oxide (NO). Additionally, ISG15 has been observed to stimulate natural killer (NK) cell proliferation and induce interferon-gamma (IFN-γ) production.
ISG15’s Diverse Roles in Health and Disease
Beyond its role in combating infections, ISG15 is involved in other cellular processes and disease states. Its expression can be altered in various human diseases, including several types of cancer. In cancer, ISG15 can have complex, even contradictory, effects.
In some contexts, elevated ISG15 levels have been associated with promoting tumor growth, metastasis, and anti-cancer drug resistance, possibly by disrupting cytoskeletal architecture or influencing the ubiquitin-proteasome pathway. Conversely, free ISG15 has shown anti-tumor effects by activating the immune system. The specific role of ISG15 in cancer often depends on whether it is in its free form or conjugated to other proteins.
ISG15 also influences inflammation, with free ISG15 increasing the secretion of pro-inflammatory cytokines like IL-8 and IL-1β. Research links ISG15 to autoimmune conditions like Systemic Lupus Erythematosus (SLE), where abnormal ISG15 expression may exacerbate inflammatory responses. These roles highlight ISG15’s implications for human health and disease.