These proteins demonstrate E3 ubiquitin ligase activity along with other non-E3 ubiquitin ligase activities.43 Among them, Trim25, an E3 ubiquitin ligase, plays a role in various physiological and pathological phenotypes, including cancer, development, and innate immunity.44 Trim25 has been reported to mediate K48- and K63-linked ubiquitination, making it a necessary and sufficient regulator for key cell events.45–47 In lung cancer, Trim25 binds to PTEN, facilitating its K63-linked ubiquitination. The gene discussed is TRIM25; the disease is cancer.