Regulation of Viral Restriction by Post-Translational Modifications

Abstract

Intrinsic immunity is orchestrated by a wide range of host cellular proteins called restriction factors. They have the capacity to interfere with viral replication, and most of them are tightly regulated by interferons (IFNs). In addition, their regulation through post-translational modifications (PTMs) constitutes a major mechanism to shape their action positively or negatively. Following viral infection, restriction factor modification can be decisive. Palmitoylation of IFITM3, SUMOylation of MxA, SAMHD1 and TRIM5α or glycosylation of BST2 are some of those PTMs required for their antiviral activity. Nonetheless, for their benefit and by manipulating the PTMs machinery, viruses have evolved sophisticated mechanisms to counteract restriction factors. Indeed, many viral proteins evade restriction activity by inducing their ubiquitination and subsequent degradation. Studies on PTMs and their substrates are essential for the understanding of the antiviral defense mechanisms and provide a global vision of all possible regulations of the immune response at a given time and under specific infection conditions. Our aim was to provide an overview of current knowledge regarding the role of PTMs on restriction factors with an emphasis on their impact on viral replication.

Keywords: degradation; intrinsic immunity; post-translational modifications; restriction factors.

Figure 1

Cells express several cellular antiviral factors that interfere with almost every step of the viral replication cycle. Schematic representation that highlights the known PTMs of those factors required for their antiviral activity. The viral proteins and PTMs antagonizing these factors are also indicated. Nef, Vpr, Vpx, S2 and Glyco-Gag are retroviral proteins, and BGLF4, U69, UL97 and ORF36 are herpesvirus-encoded kinases.

Figure 2

Schematic representation of human restriction factors, with key domains and residues involved in PTMs. For each restriction factor, the target viral step is indicated, and the modification residue and the corresponding PTM are marked with same colors. The 20 putative lysines (K) in APOBEC are K2, 40, 42, 52, 63, 76, 79, 99, 113, 141, 150, 163, 180, 249, 270, 297, 301, 303, 334 and 344. The four residues critical for Vif-induced APOBEC proteasomal degradation are indicated, although their importance remains controversial. CTD: cytoplasmic C-terminal domain; AP2: AP2 binding domain, AP: amphipathic helix; HD: hydrophobic domain; CIL: conserved intracellular loop; TM: transmembrane domain; IL: intracellular loop; EL: extracellular loop; SIM: SUMO-interacting motif; SAM: sterile alpha motif; HD domain: histidine-aspartic-containing domain; BSE: bundle-signaling element; G domain: GTPase domain; CT: cytoplasmic tail; ED: extracellular domain.

Figure 3

Regulation of human restriction factor activities and outcomes by PTMs. (A,B,C) Antiviral effects of the PTMs, (D,E,F) proviral effects of the PTMs on the restriction factors and (G) unknown outcomes and/or function of the PTMs on the restriction factors. Restriction factors with the modified residues are illustrated. For each factor, the mechanism involved, the outcome of modified factors, the effect on viruses and the viral proteins antagonizing these factors are indicated. PM: plasma membrane; NPC: nuclear pore complex.