Analysis of the TRIM5α-mediated restriction of retrotransposons

• Applicant: Professor Dr. Thomas Gramberg
• Subject Area: Virology ; Immunology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416905780

LINE-1 retrotransposons are the only autonomously active mobile genetic elements within the human genome. About 17 % of the human genome is of LINE origin and it still harbors about 100 potentially active copies. Although "jumping" of LINE-1 elements into new locations is rare, new LINE-1 insertions have been shown to cause severe genetic disorders, like hemophilia, muscular dystrophy, or cancer. The efficient control of transposable elements is therefore essential to maintain genome integrity. For the control of exogenous viral infections, cellular restriction factors are key. One of them, TRIM5α, has been shown to block various retroviruses in a species-specific manner, most likely by direct interaction with the retroviral capsid structure. While rhesus but not human TRIM5 alpha efficiently inhibits HIV-1 infection, we found that both rhesus and human TRIM5α restrict the retrotransposition of LINE-1 elements to a similar degree. This is even more surprising since intracellular replicating LINE-1 elements do not form a capsid structure, which is the classical target of the TRIM5 alpha-mediated block to retroviral infection. Thus, the inhibition of endogenous LINE-1 elements represents a novel function of the important HIV restriction factor TRIM5 alpha. Within Aim1 of this proposal, we will determine how human TRIM5a blocks endogenous LINE-1 elements and which steps of the life cycle of these elements are blocked. The block to endogenous genetic elements by TRIM5 alpha might also explain the strong positive selection of TRIM5α during evolution, which has been shown to predate the appearance of primate lentiviruses, like HIV-1. Several single nucleotide polymorphisms can be found in human TRIM5 alpha, but the only differ marginally in their ability to block HIV. Thus, within the second aim of this proposal we will ask whether the various TRIM5α alleles show a differential activity against human LINE-1. The murine genome contains a much larger number of still active endogenous retroviruses and retroelements compared to the human genome. Interestingly, the genetic locus of TRIM5 alpha also strongly expanded in mice and harbors seven different TRIM5 alpha orthologues, TRIM12a-c and TRIM30a-d. Since no virus driving this expansion has been identified so far, we will ask within the third aim of the study whether the abundance of endogenous retroviruses and retroelements in mice might be responsible for the expansion of the murine TRIM5 locus and determine the effect of the TRIM5 proteins on the replication of different endogenous retroviruses and retroelements. Together, this application will identify the mechanism how human TRIM5α blocks the replication of endogenous LINE-1 retroelements. Also, this project will clarify to what extent different alleles of human TRIM5 alpha and the different murine TRIM5 orthologues block retroelements and therefore contribute to genome stability in mice and men.

• DFG Programme: Research Grants