Post-Translational Modifications of Retroviral HIV-1 Gag Precursors: An Overview of Their Biological Role

Abstract

Protein post-translational modifications (PTMs) play key roles in eukaryotes since they finely regulate numerous mechanisms used to diversify the protein functions and to modulate their signaling networks. Besides, these chemical modifications also take part in the viral hijacking of the host, and also contribute to the cellular response to viral infections. All domains of the human immunodeficiency virus type 1 (HIV-1) Gag precursor of 55-kDa (Pr55Gag), which is the central actor for viral RNA specific recruitment and genome packaging, are post-translationally modified. In this review, we summarize the current knowledge about HIV-1 Pr55Gag PTMs such as myristoylation, phosphorylation, ubiquitination, sumoylation, methylation, and ISGylation in order to figure out how these modifications affect the precursor functions and viral replication. Indeed, in HIV-1, PTMs regulate the precursor trafficking between cell compartments and its anchoring at the plasma membrane, where viral assembly occurs. Interestingly, PTMs also allow Pr55Gag to hijack the cell machinery to achieve viral budding as they drive recognition between viral proteins or cellular components such as the ESCRT machinery. Finally, we will describe and compare PTMs of several other retroviral Gag proteins to give a global overview of their role in the retroviral life cycle.

Importance of Viral Late Domains in Budding and Release of Enveloped RNA Viruses

“…The recruitment of the ESCRT machinery by E3 ubiquitin ligases NEDD4 family is linked to the ubiquitination [ 61 , 69 , 154 , 155 , 156 , 157 ]. Indeed all retroviral Gag polyproteins, except Gag from spumaviruses [ 158 ], are ubiquitinated (for a review, see [ 159 ]), and ESCRT-0, ESCRT-I, and ESCRT-II recognize and interact with ubiquitylated cargos (for a review, see [ 160 ]). Moreover, NEDD4 interacts with the RSV PPxY L domain via its WW domain [ 69 , 161 ], and overexpression of WW domain impaired RSV budding [ 69 ], similarly to the mutations occurring in the HECT catalytic site [ 97 ].…”

The HIV-1 Gag Protein Displays Extensive Functional and Structural Roles in Virus Replication and Infectivity

“…The second signal involving PIP 2 and a cluster of basic residues localised around the cationic loop connecting β-strands one and two, otherwise known as the highly basic region (HBR; amino acids 17–31) [ 30 ], stabilizes membrane binding to the inner leaflet of the plasma membrane [ 31 ]. The HBR facilitates an electrostatic interaction between the protein and the negatively charged PIP 2 in the plasma membrane as seen in Figure 2 C [ 30 ]. The exposure of myristic acid, and thereby its insertion into the lipid bilayer, is influenced by the HBR and the PIP2 head group [ 25 ].…”

“…The exposure of myristic acid, and thereby its insertion into the lipid bilayer, is influenced by the HBR and the PIP2 head group [25]. Upon transition from sequestered to exposed, the PIP 2 30 KLKH 34 recognition site sequesters the PIP 2 fatty acid into the hydrophobic pocket (Figure 2C). The interaction between the plasma membrane and myristic acid thereby promotes the formation of a bi-directional lipid bilayer [4].…”

Visualization of Retroviral Gag-Genomic RNA Cellular Interactions Leading to Genome Encapsidation and Viral Assembly: An Overview

“…The major function of MA resides in its ability to anchor Gag proteins to the PM where the virions bud. Most retroviral Gag proteins bear an N-terminal myristyl group which is post-translationally added to the amino-terminal glycine residue in MA (for a review see [30]), and which allows hydrophobic interactions with the PM. Zhou and Resh proposed that specific Gag binding to the PM is regulated by a mechanism named "myristyl switch [31], and several other groups analyzed the molecular mechanisms promoting the exposure of the myristyl group for its insertion into the PM [32][33][34][35].…”

“…Additional retroviral domains exhibit a structural role in viral assembly or in Gag multimerization, as, for instance, the p10 domain in RSV Gag [45], or the segment p2, located between NC and CA in HIV-1 Gag [61,62] as mutations in this domain modulate packaging of spliced viral RNAs [63,64]. Finally Gag domains can also exhibit regulatory functions as the p12 domain in MLV Gag (Pr65 Gag ) that, in its mature form, tethers the pre-integration complex (PIC) to host chromatin for integration [65], the PR domain in RSV Gag that displays an enzymatic protease activity, the p8 domain in MMTV Gag which is mono-ubiquitinated [30], and the p6 domain in HIV-1 Gag that was also observed to affect Gag binding to short oligoribonucleotides [66], and to regulate Gag binding specificity to gRNA fragments [67].…”