### ISG15 Gene Overview

**Gene Symbol:** ISG15  
**Function:** ISG15 encodes a ubiquitin-like protein that is integral to the innate immune response, particularly against viral infections. It is involved in a process known as ISGylation, where it is conjugated to target proteins, thereby affecting their stability, activity, or localization.

### 1. Associations with Other Genes

Aside from those mentioned in the summaries (IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B, CHMP6, EIF2AK2/PKR, RIGI, EIF4E2, UBE2N, UBE2E1, IRF3, and FLNB), ISG15 also associates with:

- **IRF1:** Involved in the regulation of immune response.
- **IFI35:** A protein with roles in antiviral responses.
- **PRKRA:** Also known as PACT, involved in the activation of PKR.
- **TRIM family proteins (e.g., TRIM25):** Involved in ubiquitination processes and antiviral activity.

### 2. Aging and Age-Related Diseases

Research suggests that ISG15 and its associated pathways may play a role in age-related diseases and cellular senescence due to the following:

- **Inflammation:** As aging is characterized by chronic low-grade inflammation (inflammaging), ISG15 might contribute to the heightened inflammatory response observed in older individuals, potentially impacting diseases like Alzheimer's.
- **Antiviral Responses:** Older adults have a reduced immune response to viral infections, and changes in ISG15 regulation may underlie some of these deficiencies.
- **Cancer:** ISG15 has been implicated in tumor immunity and may contribute to age-related cancer pathways, though more research is required in this area.

### 3. Drug Interactions

While specific drugs directly targeting ISG15 are limited, several drug classes and compounds are known to influence ISG15 levels or its associated signaling pathways:

- **Interferons (e.g., IFN-alpha, IFN-beta):** These drugs are significant in inducing the expression of ISG15 and ISGylation processes.
- **Antiviral agents:** Drugs used for viruses like influenza and HIV, which by modulating immune responses, can result in changes in ISG15 expression.
- **Cytokine Modulators:** Therapeutic agents targeting cytokines may indirectly impact ISG15 regulation or function.

### 4. Pathways and Biological Processes

ISG15 is involved in several biological pathways:

- **Innate Immune Response:** Central to antiviral response via ISGylation.
- **Cytokine Signaling:** Particularly through secreted ISG15 acting upon immune cells.
- **Ubiquitin-Mediated Proteolysis:** Participates in the regulation of target proteins post-translational modification.
- **Negative Regulation of Viral Budding:** Role in inhibiting viral assembly and budding through interaction with viral proteins of pathogens such as HIV and Ebola.

**Biological Processes:**
- **ISGylation** (the conjugation of ISG15 to proteins).
- **Cellular response to interferon-beta (IFN-β)** and other cytokines.
- **Defense response to viruses.**
- **Cell-to-cell signaling.**
- **Chemotaxis of immune cells, particularly neutrophils.**

This multifaceted role highlights the critical importance of ISG15 in both immune response and its potential implications in various pathophysiological contexts, including viral infections and age-related conditions.