To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Abstract

The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target's function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host-virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.

Microbial and autoantibody immunogenic repertoires in TIF1γ autoantibody positive dermatomyositis

“…The presence of autoantibodies against cancerassociated TRIMs accords with the strong temporal association between myositis and the development of malignancies in adult-onset anti-TIF1γ positive DM (Oldroyd et al, 2019), consistent with the high proportion of cancer-associated myositis cases in the current study (45%). Overall, the expanded targeting of TRIM proteins we observed in DM plasma supports the role of the TRIM RING-type E3 ubiquitin ligase subfamily as powerful regulators of the immune system through post-translational modification (Hage and Rajsbaum, 2019;van Tol et al, 2017).…”

Predator: A novel method for targeted protein degradation

“…In the present study, we have developed an innovative and modularized targeted protein degradation system, the Predator system, based on the core function of Trim21 (17,19,39), and we demonstrated that this novel method could directly degrade endogenous target proteins in cells with high efficiency. Compared to Trim-Away technology which introduces antibodies into cells by microinjection or electroporation, our Predator system, through ectopic expression of modularized bifunctional molecules that functions similarly as the antibody to recruit E3 ligase Trim21 and bind to the targets with high specificity, was much more modularized and convenient, because it need only to express the designed Predator system via easy-to-use gene vectors like plasmids or virus (Fig 6) (9).…”

TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L

“…In addition, this study identified the E3-ligase TRIM25, an important mediator of anti-viral activity [ 36 , 37 ], as a mediator of CIC post-translational stability. Overexpression of TRIM25 was able to reduce CIC protein expression while siRNA knockdown of TRIM25 was able to stabilize CIC and promote its tumor suppressor function.…”