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.
References
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
No comments:
Post a Comment