A peek behind the paper – Shitao Li on TRIM proteins as antivirals

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Take a look behind the scenes of a recent Future Virology review, entitled: ‘TRIM proteins: an emerging antiviral protein family’, as we ask the authors about TRIM proteins, viral resistance and the future of this field.

What inspired you to write this review?

When I was a trainee at Harvard Medical School (MA, USA), I worked on two TRIM proteins, TRIM65 and TRIM32, and studied their roles in microRNA biogenesis and viral infection, respectively. After my laboratory was established at the Oklahoma State University (OK, USA) in 2015, I led a talented team to continue the work on TRIM proteins and recently we found another TRIM protein, TRIM41, restricts influenza A virus infection.

Due to the emerging importance of TRIM proteins in host defense, there has been a rapid growth of the studies on TRIM proteins in recent years. These proteins have been found to involve intrinsic, innate and adaptive immunity. Our lab also is an immunology lab, and we are interested in the functional role of TRIM proteins on each level of immunity. Given that most reviews of TRIM proteins don’t have a focus on different tiers of host immunity, we think a timely review of TRIM proteins with highlights of each level of host defense will benefit the field and provide insights for future studies.

Read the full review in Future Virology now >

 How do TRIM proteins function for host immunity?

There are several ways for TRIM proteins to function for host immunity. First, TRIM proteins can act as intrinsic immune factors by directly targeting viral proteins or capsids. TRIM proteins mediate proteolytic ubiquitination, such as K48-linked ubiquitination of viral proteins, which results in viral protein degradation, thus inhibiting viral infection.

Secondly, TRIM proteins participate in innate immune signaling pathways to promote type I interferon expression. In this scenario, these proteins mediate non-proteolytic ubiquitination, such as K63-linked ubiquitination, which usually provides a platform/scaffold to form an active signalosome. Interestingly, some of these TRIM proteins are also interferon-stimulated genes, which represent a positive feedback loop of innate immunity. Lastly, TRIM proteins also regulate adaptive immunity. Although the ubiquitin E3 ligase activity is required, the molecular mechanisms are yet to be determined due to limited animal models for TRIM proteins.

Is there viral resistance to TRIM protein defense?

Yes, there is. As we know, viruses always can find a way to sabotage host immune surveillance. In terms of TRIM proteins, recent studies find viruses can target TRIM proteins to inhibit host innate immune response. For instance, the non-structural protein 1 (NS1) of influenza virus interacts with TRIM25, a TRIM protein critical for viral RNA-elicited innate immunity. The interaction impairs viral RNA-induced type I interferon expression. In addition, many TRIM proteins inhibit viral infection by targeting the lysines of viral protein for ubiquitination and subsequent protein degradation. Virus could mutate the targeting lysines and evade the TRIM protein defense.

How could TRIM proteins be used for developing new antiviral therapeutics?

For developing new antiviral therapeutics, we first could induce the expression of TRIM proteins to boost host immunity. Secondly, we could screen the library of small molecules to find a drug that can activate or enhance TRIM enzymatic activity. Lastly, some viruses target TRIM protein to evade host defense. For example, the matrix protein of Nipah virus induces TRIM6 degradation to suppress TRIM6-mediated IFN response. In this regard, we could screen libraries to find inhibitors to block the interaction between viral protein and TRIM proteins.

What work are you hoping to do/ what do you think needs to be done in this area?

There are three directions that I hope to do in the future. The first one is to study the regulatory mechanisms for TRIM proteins because we have to elucidate the regulatory mechanisms before we are able to develop a novel strategy to boost host immunity by modulation of TRIM protein activity.

The second one is to study the in vivo role of TRIM proteins because most do not have an animal model. As we know, animal models are the valuable tools to study the in vivo role of TRIM proteins. Furthermore, the knowledge of the role of TRIM proteins in adaptive immunity is limited, and the major reason is the availability of animal models. The efforts to generate TRIM animal models will greatly move the field forward.

The last direction is to study the inherent relevance of the genetic mutations/variations of TRIM proteins to human immune diseases. A few studies have shown the correlation between genetic mutations of some TRIM proteins and developmental diseases. However, whether genetic mutations of TRIM proteins are linked to infectious diseases is not clear. Taken together, these directions will open new spectrum in anti-viral research and will provide a developing strategy for prevention and control of viral infections.

Read the full review

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