Arc - An endogenous neuronal retrovirus?

Abstract

The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain and has been implicated in various neurological disorders. However, little is known about Arc's evolutionary origins. Recent studies suggest that mammalian Arc originated from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestral to retroviruses. In particular, Arc contains homology to the Gag polyprotein that forms the viral capsid and is essential for viral infectivity. This surprising connection raises the intriguing possibility that Arc may share molecular characteristics of retroviruses.

Keywords: Arc; Evolution; Gag; HIV; Retrotransposon; Retrovirus; Synaptic plasticity.

Figure 1. Conservation of Gag homology domains in Arc

A. Alignment of HIV-1 MA and Arc’s putative MA domain, taken from Campillos et al, 2006 [8], using BLAST alignment of human HIV-1 (Uniprot #P03367) and rat Arc (Q63053). Sequence similarity = 18%. B. Alignment of HIV-1, Ty3/Gypsy (Q12173) and the rat Arc CA domain taken from Campillos et al, 2006 [8]. Degree of conservation is color coded, with white indicating no conservation and dark blue indicating high or perfect conservation. CA sequence similarity (HIV and Arc) = 9%. C. Domain organization of HIV-1 Gag and Arc. Arc’s putative MA domain is predicted by computational modeling [8], but not experimentally. The Arc CA domains are based on crystal structures of these fragments [7].

Figure 2. Role of the Gag polyprotein in the HIV life-cycle

HIV Gag protein self-assembles (determined by the CA domain) in the cytosol and at the plasma membrane (determined by the MA domain), while the capsid encapsulates viral RNA (via the NC domain) that is transcribed by the host cell. The immature HIV capsid is secreted in an ESCRT-dependent manner (via the p6 domain) with membrane that contains the viral envelope protein (Env). The mature HIV capsid is formed by cleavage of Gag, which results in conformational changes in the structure of the capsid. The mature virus particles bind host cells through surface receptors (such as CD4) and membrane fusion occurs. Alternatively, virus particles are first endocytosed prior to fusion and particles released into the cell after full fusion occurs in the endosome. Ultimately, viral RNA is released from the particles and is reversed transcribed into viral DNA that is integrated into the host genome via other viral proteins.