IFITM protein regulation and functions: Far beyond the fight against viruses

Abstract

Interferons (IFNs) are important cytokines that regulate immune responses through the activation of hundreds of genes, including interferon-induced transmembrane proteins (IFITMs). This evolutionarily conserved protein family includes five functionally active homologs in humans. Despite the high sequence homology, IFITMs vary in expression, subcellular localization and function. The initially described adhesive and antiproliferative or pro-oncogenic functions of IFITM proteins were diluted by the discovery of their antiviral properties. The large set of viruses that is inhibited by these proteins is constantly expanding, as are the possible mechanisms of action. In addition to their beneficial antiviral effects, IFITM proteins are often upregulated in a broad spectrum of cancers. IFITM proteins have been linked to most hallmarks of cancer, including tumor cell proliferation, therapeutic resistance, angiogenesis, invasion, and metastasis. Recent studies have described the involvement of IFITM proteins in antitumor immunity. This review summarizes various levels of IFITM protein regulation and the physiological and pathological functions of these proteins, with an emphasis on tumorigenesis and antitumor immunity.

Keywords: immunity; interferon-induced transmembrane proteins; stem cells; therapy resistance; tumor immunosurveillance; tumor progression.

Figure 1

Structures of IFITM protein family members expressed in humans. (A) Comparison of protein sequences using a multiple alignment tool (Unipro UGENE) with relevant protein domains and sites of posttranslational modifications indicated. (B) Percentage of mutual IFITM protein identity (blue) and similarity (yellow). (C) One of the proposed models of IFITM protein topology in the plasma/vesicular membrane. IMD – intramembrane domain (amphipathic helix); CIL – conserved intracellular loop; TMD – transmembrane domain. Created with BioRender.com.

Figure 2

Regulation of expression and localization of IFITM proteins. During an inflammatory response, IFITM gene expression is triggered together with other ISGs by STAT/IRF signaling pathways. In cancer cells, the expression of IFITMs is linked with activation of the Wnt/β-catenin signaling pathway which is caused by disruption of β-catenin destruction complex (APC, CKI loss of function). IFITM expression is also controlled by KLF4 inhibiting Wnt/β-catenin signaling. Another cause of increased IFITM level in tumors is promoter demethylation, on the other hand, BCL6 causes transcriptional repression of IFITM3 gene by binding to its promoter. Posttranscription regulation of IFITMs includes miRNA-directed cleavage of IFITM mRNA, which can be prevented by IFITM4P lncRNA acting as a decoy for miRNAs. Posttranslational regulation comprises a proper IFITM localization. While IFITM1 (red) is maintained in the plasma membrane, IFITM3 (blue) is endocytosed into endosomes by AP-2 recognizing its YEML motif. IFITM3 protein turnover is controlled by autophagy. Created with BioRender.com.

Figure 3

IFITM proteins have been described to affect various cancer hallmarks. The scheme shows IFITM-regulated signaling pathways and factors linked to individual hallmarks of tumor cells. Created with BioRender.com.

Figure 4

Expression levels of IFITM1, IFITM2 and IFITM3 in different types of tumors compared with adjacent normal tissue. The data used for the analyses were obtained from the GTEx Portal (https://gtexportal.org/home/) on 06.09.2021. The obtained data set was processed using Rscript, which is based on the R language (https://www.R-project.org/), and box plots of the IFITM genes were created. FKPM - fragments per kilobase million.