Tripartite the immune system. According to the evolutionary

Tripartite motif-containing proteins are a large family of proteins that
shares a conserved domain architecture consisting of an N-terminal RING domain,
one or two B-box domains and a C-terminal coiled-coil (RBCC) domain. The
conserved TRIM portion serves as a scaffold for other modules that confers
specific protein-protein interaction features. The RBCC domain is an ancient
structure, having been traced back to a metazoan ancestor (Sardiello et al.,
2008). While invertebrates have a relatively low number of TRIM, the great
number of TRIM proteins encoded by mammals witnesses the evolutionary success
of the tripartite motif as a versatile scaffold for different C-terminal
domains. The phylogenetic analysis of Sardiello and colleagues subdivided the
TRIM proteins into two groups, one containing both the B-box domains and a
C-terminus different than the SPRY motif (group 1), and the other characterized
by the presence of B2 only and a carboxy-terminal SPRY domain (group 2) (Sardiello
et al., 2008).

TRIM genes belonging to group 2 have evolved more rapidly than group 1
genes and are not present in invertebrates. Mammals encode several orthologous
TRIM proteins whereas TRIM specie-specific genes have been found among group 2
proteins. These genes have evolved through genomic rearrangements as deletions
or duplications as highlighted by the presence of some clusters of TRIM genes
in the genome of mammals. Human genome contains at least four clusters of TRIM
genes, on chromosomes 5, 6, 7 and 11. Notably, chromosome 6 contains six genes
belonging to C-V subfamily and involved in the innate immunity, clustering
together in the same region of the major histocompatibility complex (MHC)
region (Meyer et al., 2003). On chromosome 11, locus 11p15.4 includes TRIM5 and
22, currently considered primate-specific genes, which are regulated by IFN and
involved in retroviral restriction (Sardiello et al., 2008).  Many proteins in group 2 have been linked to
innate immunity, specifically to antiviral response. Given its recent appearance
and dynamicity, group 2 could rapidly respond to selective pressures caused by
viral infections, acting as a reservoir of genetic diversity that can be
exploited by the immune system.

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According to the evolutionary “Red Queen” hypothesis (Van Valen, 1974), proteins
that are directly involved into a functional antagonistic interaction with
another genetic entity are under a constant evolutionary pressure that lead to
the accumulation of nonsynonymous aminoacidic changes relatively to synonymous
changes, a phenomenon called positive selection (dN>dS) (Duggal and Emerman,
2012; Emerman and Malik, 2010).

Although positive selection is not commonly observed among host genes,
several antiviral factors contain genetic signature of this phenomenon (Bustamante
et al., 2005; Subramanian and Kumar, 2006). In this regard, both TRIM5 and
TRIM22 genes have evolved under positive selection (Sawyer et al., 2007; Sawyer
et al., 2005) and have a dynamic history of gene expansion and loss throughout
mammal evolution. In primates, both genes lie in a cluster on chromosome 11;
however, Old World Monkeys, New World Monkeys and Apes, including humans, clade
separately, and the positive selection seems to have operated in a mutually
exclusive way for each primate lineage.

In this context, is relevant that expression quantitative trait loci
(eQTLs), which are SNPs associated with variations in expression levels, have
been described as relevant in the regulation of immune system response to viral
challenges. Quach and colleagues found that the transcriptional response of
TRIM22 upon viral challenge variates between populations, despite not finding a
causative eQTL for such manifestation (Quach et al., 2016). Previously, Raj et
colleagues identified a TRIM22 eQTL in monocytes (Raj et al., 2014) further
suggesting that such regulatory SNPs could play a role in TRIM22 mediated
antiviral immunity.  

Recently, has been formulated an intriguing theory proposing that TRIM
proteins and proteins belonging to type I IFN system could have co-evolved
(Versteeg et al., 2014a). Ancestral IRF were indeed already present in early
invertebrates and their number rapidly increased and evolved to the vertebrates
under positive selection similarly to TRIM proteins, which are ISG playing a
role in triggering the innate response against pathogens (Nehyba et al., 2009).
Therefore, this parallelism could be explained by a process of at least in part
common evolution also reflected in their genomic location close to the MHC
locus in mammals, birds and fishes (Meyer et al., 2003; Ruby et al., 2005;
Vernet et al., 1993).


1.6.3 TRIM
proteins and innate antiviral immunity

increasing number of TRIM proteins had been shown to prevent or curtail
pathogen invasion (Versteeg et al., 2014a), many members are induced by both
type I and II IFN (Carthagena et al., 2009) and regulate the PRR-driven
pathways that shape the immune response to viruses, bacteria, and parasites
(Kawai and Akira, 2011; Ozato et al., 2008). 
The first description of an antiviral activity by a TRIM protein was the
discovery that TRIM5? acts as a RF responsible for the resistance of Old World
monkeys to HIV-1 infection (Stremlau et al., 2004). Since then, the focus on
other TRIM family members as potential antiviral increased. Human TRIM5? is not
active against HIV-1, but interferes with  the infection by xenotropic retroviruses (viruses
capable of replicating only in cells other than those of the host species),
thus highlighting its role in preventing zoonotic transmission of viral
pathogens. For instance, the Rhesus macaque TRIM5? (rhTRIM5?) is a strong
inhibitor of HIV-1 infection, but does not prevent infection by SIV.
Conversely, human TRIM5? strongly restricts N-MLV infection and provides a mild
restriction to HIV-2, while not interfering with HIV-1 (Hatziioannou et al.,
2004; Keckesova et al., 2004; Perron et al., 2007). These species-specific
differences in restriction are attributed to viral capsid sequence variation
between viruses, and subsequently, to the ability of TRIM5? to recognize and
bind to the viral capsid through its C-terminal PRYSPRY domain (Nakayama et
al., 2005; Perez-Caballero et al., 2005; Stremlau et al., 2006; Stremlau et
al., 2005; Yap et al., 2005. TRIM5? viral restriction occurs at early stages of
viral replication, immediately after the entry phase. Though its molecular
mechanism is still not completely understood, it is reported its binding to the
capsid lattice (CA) of the incoming retrovirus. After binding to CA examers, rhTRIM5?
restricts viral infection dependently to the proteasomal pathway, while human
TRIM5?  acts as a PRR promoting the
secretion of type I INFs. (Lukic et al., 2011; Pertel et al., 2010).  As previously mentioned, the coiled-coil
domain of TRIM proteins possesses the ability to form high molecular weight
complexes that identify subcellular compartments. TRIM19, also known as PML,
fulfills this feature by localizing within highly organized nuclear structures,
known as PML nuclear bodies (NB). TRIM19 has been associated to a number of
cellular functions, ranging from cellular protein modification to antiviral
defense (Bernardi and Pandolfi, 2007). In particular, several studies have
confirmed that also TRIM19 alone can influence the outcome of many virus
infections, including herpes simplex (Everett and Chelbi-Alix, 2007), Ebola
(Bjorndal et al., 2003), lymphocytic choriomeningitis (Bonilla et al., 2002),
Lassa (Asper et al., 2004), influenza A (Chelbi-Alix et al., 1998; Iki et al.,
2005), vesicular stomatitis (Bonilla et al., 2002), rabies (Blondel et al.,
2010), human foamy virus (Regad et al., 2001), and HIV-1 (Lusic et al., 2013). Regarding
HIV-1, TRIM19 has been recently shown to bind to the latent HIV-1 promoter at
the level of NB and to inhibit proviral transcription by anchoring the histone
methyltransferase G9a to viral DNA thereby facilitating the G9a-mediated
dimethylation of H3K9, a known mark of facultative heterochromatin within
euchromatic regions (Ott and Verdin, 2013). Indeed, HIV-1 production was
induced in latently infected resting memory CD4+ T cells by KD
TRIM19 expression, suggesting that this molecule might play an important role
in either the establishment or maintenance of HIV-1 latency. Moreover, treating
J-Lat cells with HDAC inhibitor caused the loss of co-localization between
TRIM19 NB and the HIV-1 provirus, indicating that HDAC could act in concert
with PML to repress HIV-1 transcription (Lusic et al., 2013). 

C-VI TRIM proteins 24, 28 and 33 contain a bromodomain (BRD), which can
recognize acetyl-lysines on histones and regulates chromatin remodeling and transcriptional
activation (Dyson et al., 2001; Zeng and Zhou, 2002). TRIM24 (also known as TIF1-?)
and TRIM28 (also known as KAP1) can heterodimerize and, together with
Kruppel-associated box (KRAB) domain-containing zinc finger proteins, act as
transcriptional repression by a mechanism that involves histone deacetylation
and chromatin remodeling (Nielsen et al., 1999). In addition, TRIM28 can also
inhibit both transcription by binding histone methyltransferases (Schultz et
al., 2002) and HIV-1 replication by forming a complex with the HDAC1, thus
preventing provirus integration in the host cell DNA (Allouch et al., 2011).



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