Delicate coordination of TRIM21’s dual activity in virus neutralization and signaling

TRIM21 belongs to the tripartite motif (TRIM) family of ubiquitin E3 ligases. Approximately 100 TRIM proteins exist in humans, and they all share a common domain structure composed of a RING domain that confers the E3 ligase enzymatic activity, one or two B-boxes, and a coiled-coil domain (1). Many TRIM proteins play crucial roles in antiviral immune responses, often by targeting specific viral components. For example, TRIM5α inhibits the infection of many retroviruses, including HIV-1, by binding to incoming viral capsids, leading to capsid dissociation and inhibition of reverse transcription of the viral genome. TRIM19, also known as promyelocytic leukemia protein, is a key component of subnuclear structures that restrict a variety of RNA and DNA viruses. Furthermore, TRIM proteins modulate signal transduction pathways that lead to antiviral cytokine production, ultimately contributing to the establishment of an antiviral state in both the infected and uninfected cell (1). For example, TRIM25 activates the innate immune sensor RIG-I, potentiating the production of antiviral cytokines, such as type-I interferons (IFN-α/β) (2). Recent studies demonstrated that several TRIM proteins, including TRIM5α and TRIM19, play dual roles in antiviral immunity by acting both as “effectors” that neutralize viral infection, and as “sensors” that induce innate immune signaling. It has also been shown that the ability of TRIM proteins to catalyze different types of ubiquitination is important for their effector and sensor functions. However, the molecular details of how the dual activity of TRIM proteins is temporally and mechanistically coordinated are not well understood. In PNAS, Fletcher et al. uncover a mechanism of stepwise ubiquitination and deubiquitination in synchronizing the sensor and effector functions of TRIM21, providing molecular-level insights into the antiviral activity of TRIM proteins (3).