The ERVK3-1 Microprotein Interacts with the HUSH Complex

Biochemistry. 2025 Aug 5;64(15):3372-3381. doi: 10.1021/acs.biochem.5c00023. Epub 2025 Jul 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Endogenous Retroviruses* / genetics
  • Endogenous Retroviruses* / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Protein Binding