From APOBEC to ZAP: Diverse mechanisms used by cellular restriction factors to inhibit virus infections

Abstract

Antiviral restriction factors are cellular proteins that inhibit the entry, replication, or spread of viruses. These proteins are critical components of the innate immune system and function to limit the severity and host range of virus infections. Here we review the current knowledge on the mechanisms of action of several restriction factors that affect multiple viruses at distinct stages of their life cycles. For example, APOBEC3G deaminates cytosines to hypermutate reverse transcribed viral DNA; IFITM3 alters membranes to inhibit virus membrane fusion; MXA/B oligomerize on viral protein complexes to inhibit virus replication; SAMHD1 decreases dNTP intracellular concentrations to prevent reverse transcription of retrovirus genomes; tetherin prevents release of budding virions from cells; Viperin catalyzes formation of a nucleoside analogue that inhibits viral RNA polymerases; and ZAP binds virus RNAs to target them for degradation. We also discuss countermeasures employed by specific viruses against these restriction factors, and mention secondary functions of several of these factors in modulating immune responses. These important examples highlight the diverse strategies cells have evolved to combat virus infections.

Molecular Mechanism of RNA Recognition by Zinc-Finger Antiviral Protein

“…Antiviral restriction factor proteins are part of the innate immune system and function to limit the host range and severity of virus infections (Chemudupati et al, 2019). Zinc-finger antiviral protein (ZAP) is a broad-spectrum antiviral restriction protein first characterized by its ability to inhibit murine leukemia virus replication in rat cells (Gao et al, 2002) and later found to restrict a wide range of viruses, including alphaviruses, filoviruses, hepatitis B virus, influenza A virus, and retroviruses (Bick et al, 2003;Li et al, 2017;Liu et al, 2015;Mao et al, 2013;M€ uller et al, 2007;Tang et al, 2017;Zhu et al, 2011).…”

Opposing activities of IFITM proteins in SARS-CoV-2 infection

“…Understanding virus-host interactions and immune responses will be critical for explaining the high variation in severity of COVID-19 observed in humans (Zhang, Tan et al, 2020). Type I interferon (IFN) is a critical component of the innate immune system that induces expression of hundreds of genes, many of which encode proteins with antiviral activities that block specific steps in viral replication cycles (Chemudupati, Kenney et al, 2019, Schoggins, Wilson et al, 2011. Among these are genes that encode the IFN-induced transmembrane proteins (IFITMs), including IFITM1, IFITM2, and IFITM3.…”

AIDS tedavisi için gen düzenleme çalışmaları

“…When HIV-1 or other viruses cause an infection various proteins in mammalian cells acts as restriction factors although these host factors are generally expressed weakly at infected cells (Chemudupati, et al 2019). Expressing these restriction factors simultaneously might be an alternative strategy for preventing replication of HIV-1.…”