HERC5 (HECT and RLD domain containing E3 ubiquitin protein ligase 5) functions as a crucial E3 ligase that catalyzes ISGylation, a post-translational modification involving the covalent attachment of ISG15 to target proteins 1. The primary function of HERC5 is to enhance antiviral innate immune responses by ISGylating key immune signaling proteins. Mechanistically, HERC5 ISGylates STING at K150, preventing its K48-linked ubiquitination and degradation, thereby facilitating STING activation and type I interferon responses 2. HERC5 also ISGylates the cytosolic DNA sensor cGAS at multiple lysine residues (K21, K187, K219, K458), promoting cGAS oligomerization and enhancing its enzymatic activity 3. Additionally, HERC5 ISGylates NLRP3 inflammasome components, stabilizing the protein by preventing proteasomal degradation 4. Disease relevance includes viral infections, where HERC5 demonstrates potent antiviral activity against hepatitis C, influenza A, HIV, and SARS-CoV-2 1. However, some viruses have evolved countermeasures, such as SARS-CoV-2's papain-like protease that cleaves HERC5-mediated ISGylation 2. Clinically, HERC5 shows cancer-type specific expression patterns, being highly expressed in esophageal cancer, suggesting potential as a therapeutic target 5. HERC5 also inhibits LINE-1 retrotransposition by destabilizing ORF1p 6.