Virus Budding and the ESCRT Pathway

Abstract

Enveloped viruses escape infected cells by budding through limiting membranes. In the decade since the discovery that the Human Immunodeficiency Virus (HIV) recruits cellular ESCRT (endosomal sorting complexes required for transport) machinery to facilitate viral budding, this pathway has emerged as the major escape route for enveloped viruses. In cells, the ESCRT pathway catalyzes the analogous membrane fission events required for the abscission stage of cytokinesis and for a series of “reverse topology” vesiculation events. Studies of enveloped virus budding are therefore providing insights into the complex cellular mechanisms of cell division and membrane protein trafficking (and vice versa). Here, we review how viruses mimic cellular recruiting signals to usurp the ESCRT pathway, discuss mechanistic models for ESCRT pathway functions, and highlight important research frontiers.

In vitro evolution of high-titer, virus-like vesicles containing a single structural protein

“…of vesicles into cellular multivesicular bodies (MVB) as well as other cellular processes (12). Retroviruses, paramyxoviruses, filoviruses, and rhabdoviruses have been shown to use components of the ESCRT pathway to drive budding (11)(12)(13). However, other enveloped RNA viruses including SFV and influenza virus do not use the ESCRT pathway in budding (14)(15)(16).…”

“…Prior to the evolution of capsid proteins, primitive RNA viruses may have used this budding mechanism. of vesicles into cellular multivesicular bodies (MVB) as well as other cellular processes (12). Retroviruses, paramyxoviruses, filoviruses, and rhabdoviruses have been shown to use components of the ESCRT pathway to drive budding (11)(12)(13).…”

“…Many enveloped RNA viruses use components of a cellular vesicular budding machinery to drive efficient budding from the cell surface (11)(12)(13). Short sequence motifs called late domains in their structural proteins recruit cellular protein complexes called ESCRT (endosomal sorting complex required for transport).…”

Negative membrane curvature catalyzes nucleation of endosomal sorting complex required for transport (ESCRT)-III assembly

“…CHMP4 can be recruited and activated through two different pathways in human cells. The first proceeds through ESCRT-I, ESCRT-II, and CHMP6, and the second through ALIX (3). The ESCRT-II-and CHMP6-dependent pathway functions downstream of ESCRT-I, which is in turn the essential link between HIV-1 Gag and the ESCRTs (3).…”

A novel phosphoserine motif in the LCMV matrix protein Z regulates the release of infectious virus and defective interfering particles

“…The arenavirus matrix protein Z is a multifunctional protein that drives the assembly and release of standard infectious virus (Fehling et al, 2012;Perez et al, 2003;Strecker et al, 2003) and DI particles (Ziegler et al, 2016). For many viruses, budding is controlled by one or more late domain(s) encoded in the matrix protein that recruit the cellular endosomal sorting complex required for transport (ESCRT) pathway, which drives the final membrane scission step (Votteler & Sundquist, 2013). The LCMV matrix protein encodes a single late domain, PPXY, which has been shown to be important for the formation of infectious virus-like particles (VLPs) (Perez et al, 2003).…”