Why Cells and Viruses Cannot Survive without an ESCRT

Abstract

Intracellular organelles enwrapped in membranes along with a complex network of vesicles trafficking in, out and inside the cellular environment are one of the main features of eukaryotic cells. Given their central role in cell life, compartmentalization and mechanisms allowing their maintenance despite continuous crosstalk among different organelles have been deeply investigated over the past years. Here, we review the multiple functions exerted by the endosomal sorting complex required for transport (ESCRT) machinery in driving membrane remodeling and fission, as well as in repairing physiological and pathological membrane damages. In this way, ESCRT machinery enables different fundamental cellular processes, such as cell cytokinesis, biogenesis of organelles and vesicles, maintenance of nuclear-cytoplasmic compartmentalization, endolysosomal activity. Furthermore, we discuss some examples of how viruses, as obligate intracellular parasites, have evolved to hijack the ESCRT machinery or part of it to execute/optimize their replication cycle/infection. A special emphasis is given to the herpes simplex virus type 1 (HSV-1) interaction with the ESCRT proteins, considering the peculiarities of this interplay and the need for HSV-1 to cross both the nuclear-cytoplasmic and the cytoplasmic-extracellular environment compartmentalization to egress from infected cells.

Keywords: ESCRT; HSV-1; cellular membranes; extracellular vesicles; viruses.

Figure 1

Schematic representation of the sequential steps leading to ESCRT-III polymerization and functioning. The main factors involved in each step are reported, along with the biological processes in which ESCRT-III plays a role based on its compartment-specific recruitment (light orange rectangles).

Figure 2

Schematic representation of the better-characterized cellular and viral processes (highlighted by red rectangles) that involve ESCRT-machinery or specific ESCRT factors. HAV stands for hepatitis A virus; HEV for hepatitis E virus; HSV for herpes simplex virus; EBV for Epstein–Barr virus; INM for inner nuclear membrane. The involvement of ESCRT machinery in the viral replication cycles is discussed in the next paragraphs.

Figure 3

Schematic representation of the main steps in a typical viral life cycle. The figure reports the replication of HIV-1. Upon entry into target cells, mediated by fusion of the viral envelope with the cell surface, the viral genome, which is single-stranded positive RNA (two molecules per viral particle), is partially uncoated from the virion structural proteins, although it is shielded by viral and cellular factors, not entirely known yet (pre-integration complex, PIC). PIC travels to the nucleus and, at the same time, the viral RNA is retrotranscribed by one of the viral enzymes into double-stranded DNA (provirus). Once entered the nucleus, the proviral DNA is integrated into the cellular genome and becomes part of it. Indeed, it is the cellular RNA polymerase II that transcribes the integrated provirus in mRNAs that are translated into the cytosol to give rise to the structural proteins Gag-Pol and Env. The first one drives—in concert with cellular proteins—the assembly and egress of the progeny virions. The latter enriches the viral envelope and is essential to bind the cellular receptors during the next replication round. Regulatory and accessory proteins are also translated. Furthermore, full-length genomic RNAs are also produced to be packaged into the novel budding particles. Once released in the extracellular environment, the new virions terminate their maturation, and they become infectious. Different viruses, due to the specific biological features (in a particular type of genome and presence or absence of an envelope), might differently execute the steps of their life cycle. However, the main steps remain the same: entry, uncoating, genome replication and transcription, protein translation, assembly of progeny virions, egress from infected cells. These stages may present certain differences in the different viral families, also due to the different biological features that characterize each family itself (with the type of genomic nucleic acids and presence or absence of a lipid envelope enwrapping the particle as the main ones in this context). What remains a common trait is the necessity for the virus to interact with the cellular apparatus throughout its replication. This is also the main reason why viruses can alter cell functions, thus causing a disease, and are all pathogenic.