The ERVK3-1 Microprotein Interacts with the HUSH Complex

Human endogenous retroviruses (hERVs) are noninfectious molecular remnants of ancient exogenous retroviruses that now make up 8% of the human genome. The ubiquitously expressed human ERVK3-1 locus was recently annotated as encoding a 109-amino acid endogenous retroviral Rec microprotein. However, because this locus was thought to be noncoding until recently, it is currently unknown whether the ERVK3-1 microprotein has a function in human cells. We demonstrate that the ERVK3-1 microprotein interacts with PPHLN1, a component of the HUSH complex. The HUSH complex promotes transcriptional repression of intron-less genes, which include parasitic genomic elements such as retrotransposons and endogenous retroviruses. We show that the ERVK3-1 microprotein is essential for transcriptional repression of previously identified HUSH target genes. We thus suggest that the ERVK3-1 Rec microprotein contributes to sensing or regulation of target gene expression by the HUSH complex.