The TRIMendous Role of TRIMs in Virus–Host Interactions

Abstract

The innate antiviral response is integral in protecting the host against virus infection. Many proteins regulate these signaling pathways including ubiquitin enzymes. The ubiquitin-activating (E1), -conjugating (E2), and -ligating (E3) enzymes work together to link ubiquitin, a small protein, onto other ubiquitin molecules or target proteins to mediate various effector functions. The tripartite motif (TRIM) protein family is a group of E3 ligases implicated in the regulation of a variety of cellular functions including cell cycle progression, autophagy, and innate immunity. Many antiviral signaling pathways, including type-I interferon and NF-κB, are TRIM-regulated, thus influencing the course of infection. Additionally, several TRIMs directly restrict viral replication either through proteasome-mediated degradation of viral proteins or by interfering with different steps of the viral replication cycle. In addition, new studies suggest that TRIMs can exert their effector functions via the synthesis of unconventional polyubiquitin chains, including unanchored (non-covalently attached) polyubiquitin chains. TRIM-conferred viral inhibition has selected for viruses that encode direct and indirect TRIM antagonists. Furthermore, new evidence suggests that the same antagonists encoded by viruses may hijack TRIM proteins to directly promote virus replication. Here, we describe numerous virus–TRIM interactions and novel roles of TRIMs during virus infections.

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

“…Ubiquitin is a 76 amino acid (aa) protein and is able to interact with targets through covalent bonds (anchored ubiquitin) or non-covalent associations (unanchored ubiquitin) [4,5,14].…”

“…In the final stage, interaction between the E2 and one of over 600 E3 ubiquitin-ligating enzymes allows for the transfer of ubiquitin from the E2 onto the target protein ( Fig. 2) [4,5,15,17]. The E2 and E3 enzymes can be expressed in a tissue-or cell-type-specific manner, and this may also depend on stimulus, including virus infection.…”

“…Formation of polyubiquitin is made possible by covalent interactions between the C-terminal Gly of one ubiquitin and one of seven Lys residues on another ubiquitin (K6-, K11-, K27-, K29-, K33-, K48-and K63-linked polyubiquitin). Alternatively, the C-terminal Gly of one ubiquitin can covalently bind the N-terminal methionine (Met) of another ubiquitin to form 'linear' polyubiquitin (M1-linked polyubiquitin) [4,5,11,17]. Furthermore, the ubiquitin machinery is capable of synthesizing polyubiquitin chains that are not covalently bound to a substrate (unanchored polyubiquitin).…”

“…These unanchored polyubiquitin chains are unique as they retain their free C-terminal Gly, typically conjugated to a substrate's Lys. This absence of direct conjugation allows unanchored ubiquitin to function as a three-dimensional signal that can be amplified by multiple non-covalent interactions with specific signalling factors [4,5,7,17,18].…”

“…1). Although we focus on current developments within the tripartite motif (TRIM) field, other excellent reviews that focus more on the antiviral aspects of TRIMs and that highlight older studies are also available [2][3][4][5][6][7][8][9][10].…”