The coevolution of mammals and viruses has been an arms race of sorts. Part of our defense against viruses comes from the innate immune response, which includes specific cell types and intracellular factors. Protein signals like interferon (IFN) can activate the expression of many genes called interferon-stimulated genes (ISGs) that have antiviral or antimicrobial activity—to limit viral, bacterial, or parasitic replication in cells—through various mechanisms. The ISGs with the highest expression are Mx proteins, which have broad antiviral activity against herpesviruses, influenza virus (flu), measles, hepatitis B, and others. Mx proteins are related to dynamin proteins that have key functions in cell remodeling. In general, the process of cell remodeling is important for cells to adapt, repair and maintain their integrity while also functioning as defense mechanisms against viruses.
Mx proteins are not the only ISGs to have broadly relevant roles for cells. In fact, two other genes, STING and cGAS, are important for sensing the presence of foreign DNA, which is broadly relevant both as an antiviral response and as a response to cancer or cell damage. While these other ISGs—STING and cGAS—have been well studied in the context of mammalian cells and other vertebrates, they were only recently identified in bacteria and in invertebrate species—animals lacking a spine like insects—that predate vertebrates. To better understand how the most abundant ISG, Mx proteins, evolved, researchers in the labs of Drs. Harmit Malik and Michael Emerman, Professors in the Basic Sciences and Human Biology Divisions at Fred Hutchinson Cancer Center, sought to discover the earliest ancestor for Mx proteins. They found that Mx-like proteins pre-date the IFN system in animals, exist in invertebrate species, and can even be found in plants and fungi! These findings were published recently in PNAS.
Just like knowing someone’s parents can tell us a lot about a person, understanding the ancestry of protein families—the organisms and environments that guide protein evolution—can help us understand protein functions in higher-order, complex organisms. To find the root of the Mx protein ancestral tree, the researchers started by finding dynamin family genes—a broader family that includes the Mx genes—within animal species. To do this, they searched for genetic sequences similar to the Mx genes in genome sequence data for many animal species. The dynamin family of genes can be separated into five distinct groups—Mx, Dyn, Drp1, Opa1, and Mfn—based on protein domains. All gene groups retain the GTPase domain, but these groups are divided by the presence or absence of a GTPase effector, Pleckstrin homology (PH), or fuzzy onion (Fzo) domain. The GTPase domain is present in all dynamin proteins; thus, all dynamin-related proteins retain this activity despite localizing to different sites within a cell to carry out distinct roles. Other domains include the GTPase effector domain that can either positively or negatively influence GTPase activity, the PH domain that aids in intracellular signaling, and the Fzo domain that enables the dynamin protein to remodel mitochondria—the energy powerhouse in cells. These five groups of dynamin genes were found in both vertebrates and invertebrates. Expansion of this search also identified dynamin-like genes in plants and fungi, as well as amoeba, plankton, algae, and single-cell eukaryotes! Together, these findings identified the existence of these dynamin-like genes prior to the existence of IFN, which is essential for the expression of the Mx genes in human cells.
The researchers were also curious about dynamin-like genes in eukaryotic viruses. Viruses can acquire host genes through horizontal gene transfer (HGT) as a part of the arms race between the host and the virus. In support of HGT occurring between virus and host for the dynamin-like genes, the researchers uncovered four examples of large DNA viruses sharing similar dynamin-like genes with amoeba, plankton, algae, and single-cell eukaryotes. Intriguingly, all the dynamin-like genes within the large DNA viruses retain the catalytic residues within the GTPase domain, suggesting that this activity is conserved in these viruses. The group of large DNA viruses that have dynamin-like proteins may require these for packaging their large genomes into the viral capsid or for the process that remodels cell membranes into envelopes that encapsulate the viral capsid. This physical barrier protects the viral genome from environmental assaults and allows the virus particle to infect a new cell.
“There are two exciting discoveries from this work,” shared Dr. Caroline Langley, a previous graduate student in the Malik and Emerman labs. “First, Mx dynamin-like genes, which play a key antiviral role in vertebrates, are much older and present in many eukaryotic species. Second, viruses have repeatedly stolen many dynamin-like genes. Thus, battles over dynamin-like functions are an ancient, ongoing conflict between hosts and viral genomes.”
Peter Dietzen, a graduate student in the Malik and Emerman labs, expanded on how these findings open new avenues of research. “We are particularly interested in characterizing these newly discovered Mx dynamin-like genes in invertebrates, fungi, plants, and basal eukaryotes. We found many cases of fungi with Mx-like genes, including the human pathogen A. fumigatus, which has multiple copies. Studying their functions in fungi could also answer important unknowns about Mx functions in animals.”
What’s next? “We would love to start characterizing these diverse Mx-like homologs in collaboration with fungal biologists or by transporting these genes into animal cells,” shared Dr. Malik. “This [work] is part of a long-standing collaboration between the Malik and Emerman labs, who have expertise in evolution and virology, respectively,” concluded Dr. Malik.
The spotlighted research was funded by the University of Washington Cellular and Molecular Biology Training Grant, Howard Hughes Medical Institute, American Foundation for AIDS research Mathilde Krim Fellowship in Biomedical Research, National Institutes of Health.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Michael Emerman and Harmit Malik contributed to this work.
Langley CA, Dietzen PA, Emerman M, Tenthorey JL, Malik HS. 2025. Antiviral Mx proteins have an ancient origin and widespread distribution among eukaryotes. PNAS. 122(4):e2416811122.
Science spotlight writer Annabel Olson is a postdoctoral research fellow in the Nabet lab at Fred Hutchinson Cancer Center. Her research focuses on studying the mechanisms that drive cancer development for both genetic and virus-associated cancers. A key tool in her research is the use of targeted protein degradation to dissect dysregulated signaling pathways in cancer and to double as a relevant pre-clinical therapeutic platform.
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