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.

Keywords: Interferon stimulated gene; Restriction factor; Virus infection.

Fig. 1

Antiviral restriction factors utilize diverse functional domains and structural features. Domain architecture for individual restriction factors are shown with amino acid lengths and the multimeric state in which the protein possesses restriction activity. Abbreviations: CD, catalytic domain; *indicates enzymatic activity; TM, transmembrane domain; NLS, nuclear localization sequence; BSE, bundle signaling element; GED, GTPase effector domain; SAM, sterile alpha motif (in SAMHD1) or S-Adenosyl methionine (in Viperin); GPI, glycosylphosphatidylinositol; CxxxCxxC, Fe-S binding motif containing three cysteine residues separated by any amino acids (x); C-term, C-terminal domain; PARP, poly(ADP-ribose) polymerase; CaaX, prenylation consensus site comprised of a cysteine residue followed by two aliphatic amino acids, and any amino acid. HD, CCCH, and WWE domains are named for specific amino acid sequence elements.

Fig. 2

Restriction factors inhibit virus replication at multiple stages of the viral life cycle. The replication cycle of a retrovirus is depicted and inhibition of specific life cycle stages by individual restriction factors is indicated. IFITM3 inhibits virus fusion and is also incorporated into nascent virion membranes to limit the fusogenicity/infectious potential of the virus. IFITM3 is primarily associated with inhibition of fusion at virus endosomes, but is shown here inhibiting fusion at the cell surface for graphical simplicity. SAMHD1 depletes dNTPs thereby inhibiting viral reverse transcription. APOBEC3G blocks reverse transcriptase processivity and also deaminates/hypermutates viral ssDNA. APOBEC3G associates with viral genomic material and is packaged into nascent virions, thus allowing its activity to impair replication in newly infected cells. MxB interacts with viral proteins and prevents nuclear import and integration of reverse transcribed viral DNA. ZAP interacts with viral RNAs possessing CG dinucleotide sequences and targets them for degradation. Viperin affects membrane composition to affect virus budding and also enzymatically produces a small molecule that inhibits viral RNA polymerases. Tetherin provides a physical tether preventing nascent virions from being released from the cell. Viral countermeasures active against these proteins are not depicted.