Budding of Enveloped Viruses: Interferon-Induced ISG15—Antivirus Mechanisms Targeting the Release Process

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 scission to release VLPs from the cellular membranes. Step 5: The ESCRT-III subunits recruit the AAA ATPase, VPS4, and the coactivator protein LIP5 to mediate the disassembly of membrane-bound ESCRT complexes concomitant with the budding process.