A human endogenous retrovirus encoded protease potentially cleaves numerous cellular proteins

The human genome consists of considerable portions derived from retroviruses typically inherited already for millions of years. So-called human endogenous retroviruses (HERVs) are usually severely mutated, yet some coding-competent HERV sequences exist. The HERV-K(HML-2) group includes evolutionarily young proviruses that still encode typical retroviral proteins. HERV-K(HML-2) has been implicated in various human diseases because transcription is often upregulated and encoded proteins are known to affect cell biology. HERV-K(HML-2) protease has received little attention so far. With findings for Human Immunodeficiency Virus (HIV) protease in mind we set out to identify human cellular proteins being substrates of HERV-K(HML-2) protease employing a modified Terminal Amine Isotopic Labeling of Substrates (TAILS) procedure. Thousands of significantly processed human proteins were revealed by TAILS and we could verify cleavage of a majority of selected human proteins in vitro. Our analysis suggests that hundreds, if not thousands of cellular proteins are potential substrates of HERV-K(HML-2) protease. As identified proteins participate in diverse, often disease-relevant cellular processes, it is conceivable that expression of HERV-K(HML-2) protease has functional consequences for cell biology and thus development of human diseases. Endogenous retrovirus-encoded protease may also be relevant for disease development in species other than human.