Interferon-induced transmembrane proteins, or IFITMs, are a family of proteins that serve as a component of the body’s innate immune response. These proteins are among the first responders when a virus is detected, as their production is triggered by signaling molecules called interferons.
The primary function of IFITM proteins is to prevent viral invaders from completing the first step of infection. They act as frontline defenders against a wide array of viruses. This mechanism is a general defense, not tailored to a specific type of virus, making IFITMs a broad-spectrum antiviral system.
The Antiviral Defense Mechanism
IFITM proteins work by preventing a virus from fusing its own membrane with the host cell’s membrane. This fusion is a necessary step for many viruses to release their genetic material into the cell and begin replication. IFITMs embed themselves within the cell’s membranes, altering their physical properties to make them resistant to viral entry.
The defensive action involves changing the flexibility and shape of the cellular membrane. By inserting into the membrane, IFITM proteins increase its rigidity and positive curvature. This alteration makes it physically difficult for the virus to merge with the cell, similar to trying to merge two soap bubbles where one has a hardened patch on its surface.
A part of this mechanism is a structural feature within the protein known as an amphipathic helix. This short, conserved region allows the protein to insert into and modify the membrane environment. The amphipathic nature of this helix, meaning it has both water-attracting and water-repelling properties, allows it to interact with the lipid bilayer of the cell membrane, directly interfering with the fusion process that viruses rely on.
The IFITM Protein Family
The IFITM family in humans consists of several members, but three are known for their antiviral roles: IFITM1, IFITM2, and IFITM3. These proteins are similar in structure but are stationed at different locations within the cell, allowing them to defend against viruses at multiple potential entry points.
IFITM1 is found on the outer surface of the cell, the plasma membrane, acting as a first line of defense against viruses attempting to enter directly. In contrast, IFITM2 and IFITM3 are located in the membranes of internal compartments called endosomes and lysosomes. Many viruses are transported into these compartments after entering a cell, and IFITM2 and IFITM3 serve to trap them there.
While the family is known for immunity, not all members specialize in fighting pathogens. For example, IFITM5 has a distinct function related to bone development and mineralization. Another member, IFITM10, has no currently known role in the immune system, demonstrating that these proteins have evolved diverse roles beyond viral defense.
Role in Viral Diseases
IFITM proteins restrict a wide range of viruses, including those responsible for significant human diseases like influenza, Dengue, HIV, and various coronaviruses. The presence and function of these proteins can impact the outcome of a viral infection, determining whether an infection remains mild or progresses to a severe state.
The connection between IFITM proteins and disease severity is understood in the context of influenza. Research has identified a specific genetic variation (SNP) in the IFITM3 gene, rs12252. Individuals who carry the ‘C’ version of this SNP produce a less effective form of the IFITM3 protein, resulting in a weakened cellular defense. Consequently, people with the rs12252-C variant are more susceptible to severe influenza infections. This genetic link helps explain why the same virus can cause a mild illness in one person and a severe condition in another.
The Paradox of IFITM Proteins
While IFITM proteins are established antiviral defenders, some viruses have evolved to turn this defense into an advantage. The presence of IFITM proteins can, in some cases, enhance the ability of certain viruses to enter a host cell. This phenomenon has been observed with specific coronaviruses, where IFITMs facilitate infection rather than block it.
This enhancement is an evolutionary adaptation by the virus. For instance, the human coronavirus HCoV-OC43, a cause of the common cold, can use IFITM2 and IFITM3 as entry factors to infect cells more efficiently. The virus appears to have co-opted the host’s cellular machinery for its own benefit.
The mechanisms determining if an IFITM protein will inhibit or enhance infection are complex, depending on the specific virus and its entry pathway. For SARS-CoV-2, the virus that causes COVID-19, IFITM proteins are restrictive. However, the balance can shift depending on other cellular factors, illustrating the context-dependent nature of these protein interactions.