Role of APOBEC3B in the Innate Immune Response

The APOBEC3 enzymes are a family of cytosine deaminases that convert cytosine to uracil on DNA or RNA and function as a vital part of mammals’ innate immune system. They provide an innate immune barrier against DNA and RNA viruses, retroviruses, retrotransposons, and other viral pathogens by inducing mutations in the virus genomes to stop their replication and protect cell integrity. APOBEC3 enzymes have evolved different preferences for DNA or RNA sequences and structures to fight against diverse viruses that cells may encounter. Many viruses, such as HIV-1, hepatitis B virus, and SARS-CoV-2, have been found to accumulate APOBEC- driven hypermutations in their genomes.

However, mutations induced by APOBEC3 enzymes are a double- edged sword, as a high level of mutations blocks viral replication by inducing lethal alterations, but a lower level of mutations promotes virus evolution and the production of new viral variants with improved features, allowing them to escape cell defense mechanisms. Remarkably, APOBEC3 enzymes also protect cells against viruses through non-canonical pathways without mutating their genomes, suggesting that APOBEC3 enzymes have evolved other mechanisms to inhibit viruses without promoting their evolution, transcending the simple model of APOBEC3s inducing mutations in viral genomes to stop their replication. Yet, the different mechanisms by which APOBEC3 members suppress viral infection without editing their genomes are still poorly understood. Our goal is to identify novel APOBEC3B anti-viral functions that do not require their deaminase activity.

We hypothesize that APOBEC3B RNA binding activity is critical in suppressing RNA virus replication by acting as a viral RNA sensor to promote the activation of the innate immune response. Our preliminary results showed that APOBEC3B promotes PKR activity after different types of RNA virus infections. Based on these results, we propose to 1) explain how APOBEC3B modulates the PKR signaling pathway to promote translation arrest, and 2) determine whether APOBEC3B suppresses RNA virus replication. This study will reveal for the first time that APOBEC3B is critical to protecting our cells against RNA virus infection without editing their genomes alongside its function against DNA viruses and retroviruses.

The long-term goal resulting from this study is the development of therapeutic strategies to suppress RNA virus replication by exploiting APOBEC3B antiviral activity.

Grant Number: 5R21AI185033-02
NIH Institute/Center: NIH
Principal Investigator: Remi Buisson