The long terminal repeat of an endogenous retrovirus induces alternative splicing and encodes an additional carboxy-terminal sequence in the human leptin receptor

The evolution of mammalian protein structure and regulation, specifically transcriptional and posttranscriptional regulation, may include among its tools the use of abundant retroviral long terminal repeats (LTRs). In particular, LTRs may be turned into switches for alternative splicing. This type of regulatory pathway is illustrated by the alternative splicing in the human leptin receptor (OBR). The human leptin receptor is involved in the control of important biological processes including energy expenditure, production of sex hormones, and activation of hemopoietic cells. OBRa and OBRb are the two major, alternatively spliced forms of the leptin receptor, called the "short form" and the "long form," respectively. We report that the OBRa short form is the result of a double splicing event which occurs within the LTR of the endogenous retrovirus HERV-K. Working as a switch of alternative splicing, this LTR also encodes the terminal 67 amino acid residues in OBRa. We suggest the possibility of transcriptional and posttranscriptional regulation of OBR expression by steroids that bind the LTR.