Abstract
Many cellular factors that potentially interfere with the progression of retroviral infections have been identified in mammals. Restriction factors expression is often induced by interferon, which is the first line of the host’s innate immune response. Among them, the species-specific restriction factor TRIM5α, is able to block lentiviral infections by binding directly to the incoming retroviral capsid. However, although identified in 2004, the molecular details of its antiviral action remain to be defined.In order to identify potential cofactors involved in this restriction, we have developed loss-of-function genetic screens in haploid cell line HAP1 and identified several candidates including PRELID3A. We confirmed that inactivation of PRELID3A by CRISPR/Cas9 or siRNA significantly impairs TRIM5α restriction of murine N-MLV, equine EIAV and feline FIV viruses in human cells, and HIV-1 in simian cells. Besides, PRELID3A has also an effect on the restriction of infections by two HIV sensitive to human TRIM5α (HIV-1 G89V mutant and HIV-2ROD) in HAP1 cells.Very few data exist on PRELID3A. It has been suggested that this protein, like the other PRELID proteins (1, 2, 3B and 4), plays a role in fatty acid transport in the mitochondrial intermembrane space by being complexed to the TRIAP1 protein. PRELID3A is thought to be involved in the transport of the phosphatidic acid required for cardiolipin synthesis. We showed that PRELID3A was highly expressed in the mitochondrial fraction of HAP1 cells, suggesting a similar role in lipid transport. Surprisingly, we were also able to observe that PRELID3A was present at the cytoplasmic level. Using RNA interference, we assessed the involvement of different proteins in the TRIAP1-PRELID complex in restriction, and observed that some proteins in this complex may be involved in TRIM5α-mediated viral restriction. These results suggest a possible involvement of the TRIAP1-PRELID complex and mitochondria in the control of TRIM5α-mediated viral infection. However, our results showed that inhibition of TRIAP1 (depending on cell type and virus) and cardiolipin synthesis did not result in removal of restriction, suggesting that another mitochondrial function of PRELID3A or a novel cytoplasmic function of PRELID3A may be involved in TRIM5α-mediated viral restriction.