Sunday, December 16, 2012

TRIM Family Proteins: Species-specific Antiviral Function

The tripartite motif (TRIM) family is an extensively evolved protein family in metazoans. The proteins from TRIM family have been found in a variety of species, from human to worms and flies. The human TRIM proteins seem to be highly complicated from the evolutionary point of view: there present as many as 65 members of human-origin, compared with less homologues in worms (20 members) or flies (<10 members). However, 65 is not a fixed number, based on the diversity of the domain composition of the proteins. It is possible that several TRIM family proteins are difficult to identified, even though they all derived from a common ancestral gene.

TRIM proteins have multiple antiviral strategies, affecting several stages in the virus life cycle, including viral entry, viral gene expression or viral release. The strategies are based on their structures. TRIM family proteins have a relatively conserved structure, which is named RBCC motif. RBCC motif is composed of a RING domain, one or two B-boxes and a coiled-coil region. Many RING domains have ubiquitin E3 ligase activities, which have considered critical for anti-viral function of TRIM family. This ubiquitin E3 ligase activity can covalently attach ubiquitin to target proteins, and then mediate the proteasome-mediated degradation. Some RING domains, like the RING domain of TRIM 19 and TRIM 63, are also reported to evolve in sumoylation. The ubiquitylations and sumoylations of target proteins induce the downstream signaling pathways (such as IFN, PRR, RIG-I, MDA5, TLR pathways) that are associated with innate immunity.

In addition to the function of RING domain, the domains in C-terminal of the protein play a role in anti-viral activity. For example, the PRYSPRY domain can help the restriction of uncoating of the pre-integration complex by recognizing sequences that are presented on the viral capsid.

As for species-pathogen relationship, the function of TRIM family proteins is species-specific. For example, the TRIM5a from human shows inhibition at the pre-reverse transcription step of murine leukemia viruses (MLV), but shows inefficient inhibition of HIV. In contrast, the TRIM 5a from African green monkey has anti-viral effect on HIV, MLV, and EIAV.

As for the entire family of TRIM, most of the TRIM proteins particularly affect retroviruses, but some TRIM proteins also have the anti-viral activities against other viruses. Promyelocytic leukaemia (PML, or TRIM 19) is proved to have versatile antiviral function by a complicated mechanism. It has effect on retrovirus as well as influenza virus, Ebola virus, vesicular stomatitis virus, Rabies virus, et al.

This picture depicts the antiviral function of TRIM family in HIV infection.

Nisole, S. (2005). TRIM family proteins: Retroviral restriction and antiviral defence. Nature Reviews Microbiology, 3(10), 799. doi:10.1038/nrmicro1248
Ozato, K. (2008). TRIM family proteins and their emerging roles in innate immunity. Nature Reviews.Immunology, 8(11), 849. doi:10.1038/nri2413

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