Research Group of T. Gramberg

The SAM and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that plays a crucial role in a variety of different cellular functions. Besides balancing intracellular dNTP concentrations, facilitating DNA damage repair, and dampening excessive immune responses, SAMHD1 has been shown to act as a major restriction factor against various virus species. In addition to its well-described activity against retroviruses such as HIV-1, SAMHD1 has been identified to also reduce the infectivity of different DNA viruses such as the herpesviruses CMV and EBV, the poxvirus VACV, or the hepadnavirus HBV. While some viruses are efficiently restricted by SAMHD1, othershave developed evasion mechanisms thatantagonize the anti-viral activity of SAMHD1. Within this review, we summarize the different cellular functions of SAMHD1 and highlight the countermeasures viruses have evolved to neutralize the restriction factor SAMHD1.

In the years and decades following Barbara McClintock’s seminal work in the 1950s on mosaicism in maize, it became clear that mobile genetic elements, or transposons, are a major part of all eukaryotic genomes. Evolutionary speaking, replicating genetic elements are very successful, and in the case of the human genome, repetitive, transposon-derived sequences make up almost 50% of its size. Previously disregarded as just being junk DNA, it is now evident that transposable elements played, and still play, an important role in shaping structure and function of our genome. However, depending on the site of integration, retrotransposition events can also destabilize genome integrity and cause disease. Thus, cells have evolved multiple countermeasures to hold retroelements at bay and developed mechanisms to recognize retrotransposition as potential threat. Most transposons found in the human genome became inactivated over the course of evolution. The only actively transposing elements known in humans today belong to the group of non-LTR retrotransposons, most importantly the long interspersed element 1 (LINE1) and Alu elements.

We found that the host factor TRIM5α senses and restricts LINE-1 retroelements. Previously, TRIM5α has mainly been described as antiretroviral restriction factor. Most notably, rhesus TRIM5α is well-known to efficiently block HIV-1 replication, while human TRIM5α is less active. Surprisingly, we found that both human and rhesus TRIM5α efficiently repress human LINE-1 retrotransposition. TRIM5α interacts with LINE-1 ribonucleoprotein complexes in the cytoplasm, which is essential for restriction. In addition, we found that TRIM5α induces innate immune signaling (AP-1; NF-κB) upon interaction with LINE-1. Thus, our findings identify TRIM5α as pattern recognition receptor and restriction factor against endogenous mobile genetic elements, such as LINE-1. Recently, we were able to confirm and extend this activity. We found that a frequent polymorphism (SNP) in TRIM5a, H43Y, blocks LINE-1 retrotransposition with even higher efficiency than WT TRIM5a. Upon sensing of LINE-1 complexes in the cytoplasm, TRIM5a H43Y activates both NF-kB and AP-1 signaling pathways more potently than the WT allele, thereby triggering a strong block to the LINE-1 promoter. Interestingly, the H43Y allele lost its antiviral function suggesting that its enhanced activity against endogenous LINE-1 elements is the driving force behind its maintenance within the population. Thus, our study suggests that the H43Y variant of the restriction factor and sensor TRIM5a persists within the human population since it preserves our genome from uncontrolled LINE-1 retrotransposition with higher efficiency.