Pathogenic strains of viruses that infect humans are encapsulated in membranes derived from the host cell in which they infect. After replication, these viruses are released by a budding process that requires cell/viral membrane scission. As such, this represents a natural target for innate immunity mechanisms to interdict enveloped virus spread and recent advances in this field will be the subject of this paper. 1. Budding of Retroviruses Retroviruses, such as human immunodeficiency virus type 1 (HIV-1) and avian sarcoma/leukosis virus (ASLV), bud from cells using a similar mechanism (see Figure 1). Monoubiquitination of viral Gag polyproteins, catalyzed by an E1, E2, and E3 ubiquitin ligase complex, is important in the process where the ubiquitin most likely serves as a ligand for assembly of various protein budding complexes [1–5]. A recent study, however, has presented evidence that either ubiquitination of Gag or ubiquitination of transacting proteins can be used to assemble downstream virus-budding complexes . Ubiquitin is a 76-amino-acid cell regulatory protein that is conjugated to proteins at lysine residues. Free ubiquitin in the cytosol is activated in an ATP-dependent reaction by an E1 enzyme, which then transfers the ubiquitin to a cysteine residue of an E2 ubiquitin-conjugating enzyme. The E2 protein interacts with a specific E3 ubiquitin ligase, which selects the target protein for the covalent transfer of the ubiquitin. Figure 1: Parallel pathways used by ASLV and HIV-1 Gag to bud from cells. Retroviruses recruit components of the ESCRT machinery to assemble budding complexes. Step 1: HIV-1 and ASLV Gag L-domains bind to Tsg101 and Nedd4, respectively. They also bind the Alix adaptor protein. Whether these initial interactions take place in the cytosol or at the plasma membrane remains to be defined. Step 2: Nedd4 mediates ubiquitination of ASV Gag. HIV-1 Gag is ubiquitinated by an unidentified E3 ligase. Step 3: Gag oligomerization in the cytosol increases membrane avidity and in conjunction with the M domain signal at the N-terminus of Gag targets the polyproteins to sites of assembly/budding on the plasma membrane. ASLV Gag assembles on rhodamine labeled phosphatidylethanolamine (N-Rh-PE)-positive, endosome-derived membranes. HIV-1 Gag assembles on N-Rh-PE-negative membranes. Step 4: The ASLV Gag/Nedd4/Alix complex recruits ESCRT-II proteins while the HIV-1 Gag/Tsg101/Alix complex recruits the remainder of the ESCRT-I proteins. Each early budding complex then recruits the same ESCRT-III machinery which promotes the membrane
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