Emerging roles of FAM14 family members (G1P3/ISG 6-16 and ISG12/IFI27) in innate immunity and cancer

Abstract

Interferons (IFNs) manifest their cellular functions by regulating expression of target genes known collectively as IFN-stimulated genes (ISGs). The repertoires of ISGs vary slightly between cell types, but routinely include a core of common ISGs robustly upregulated in most IFN-treated cells. Here, we review the regulation and cellular functions of 2 related ISGs, ISG12 (IFI27) and G1P3 (ISG 6-16), that are commonly induced by IFNs in most, if not all, IFN-responsive cells. On the basis of sequence similarity, they are grouped together within the newly defined FAM14 family. Emerging data on ISG12 and G1P3 suggest that both are mitochondrial proteins with opposing activities on apoptosis that may influence the innate immune responses of IFNs. The G1P3 gene encodes a low molecular weight mitochondrial protein that may stabilize mitochondrial function and oppose apoptosis. In contrast, ISG12 expression may sensitize cells to apoptotic stimuli via mitochondrial membrane destabilization. On the basis of these results and differences in induction kinetics between ISG12 and G1P3, we have proposed a model for the role of these genes in mediating cellular activity of IFNs.

FIG. 1.

Putative ISG12 domain and phylogenic classification of FAM14 family members. (A) Alignment of putative ISG12 motifs of ISG12 and G1P3. The consensus sequence for the ISG12 motif (Pfam accession no. PF06140) of ISG12 and G1P3 are aligned. Black squares represent sequence identity and gray squares represent sequence similarity. (B) Phylogenetic alignment of the FAM14 family members with putative ISG12 motif. Phylogenetic alignment of FAM14 family members was curated from Tree families database (www.treefam.org). Boxes in the protein multialignments at right correspond to the putative ISG12 domains and thin lines to nondomain regions. Dark lines or boxes represent regions of identity; open or white areas indicate gaps. Vertical dark lines indicate locations of intron–exon splicing boundaries. ISG, interferon-stimulated genes.

FIG. 2.

Alignment of ISG12 isoforms. Alignment of human ISG12a, b, and c to identify consensus amino acid sequence. Black squares represent sequence identity, gray squares represent sequence similarity, and numbers indicate amino acid position. Within the consensus row, amino acids conserved in all 3 proteins are highlighted with an asterisk, while positions in which amino acids are conserved in 2 of the 3 proteins are indicated with a dot.

FIG. 3.

Elements of G1P3 gene and protein. (A) Transcriptional and coding elements of the G1P3 gene. Graphic view of the genomic sequence of the G1P3 gene spanning ∼6.14 kb from the human genome browser. The promoter region of G1P3 is analyzed by ALLGEN promo (http://alggen.lsi.upc.es/) software. (B) Structural features of G1P3 protein. Putative mitochondrial targeting signal peptide, hydrophobic, and hydrophilic domains of G1P3. Surface probability analysis by Emini's method suggests the propensity of HL-1 and HL-2 amino acids to be exposed to solvent. Numbers in parentheses of each domain represent amino acid numbers of G1P3 protein.

FIG. 4.

Model for the role of G1P3 and ISG12 in the modulation of IFNs antiviral response. In this model, G1P3 is induced at early time points after viral infection and serves to stabilize mitochondrial membrane potential, resist apoptosis, and sustain the production of IFNs through the RIG-I/MAVS pathway. ISG12 is induced at later time points of postinfection and destabilizes mitochondrial membrane potential, curtails RIG-I signaling, induces apoptosis, and downregulates IFNs production. IFN, interferon; RIG-I, RA inducible gene I.